Substituted pyrrolopyridine JAK inhibitors and methods of making and using the same

ABSTRACT

The present invention relates to new pyrrolopyridine compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of JAK1 and JAK3 kinase activity in a human or animal subject are also provided for the treatment diseases such as pruritus, alopecia, androgenetic alopecia, alopecia areata, vitiligo and psoriasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/581,428 filed Nov. 3, 2017 and U.S. Provisional Application No.62/670,448 filed May 11, 2018. The disclosures of both of theseapplications are incorporated herein by reference. The disclosure of theapplication is incorporated herein by reference.

SUMMARY

Embodiments herein are directed to having the structures of Formulas(I)-(IV), or a derivative thereof, where the R groups, ring labels, andn values are defined herein:

Disclosed herein are new pyrrolopyridine compounds and compositions andtheir application as pharmaceuticals for the treatment of disease.Methods of inhibition of JAK1 and JAK3 kinase activity in a human oranimal subject are also provided for the treatment of JAK1 and/orJAK3-mediated conditions.

The Janus Kinases (JAKs) are a subgroup of non-receptor tyrosine kinasesthat are essential to transducing signals originating from type I andtype II cytokine receptors and whose enzymatic activity is essential forthe biological activity of the cytokines. The JAK kinase family consistsof four family members: JAK1, JAK2, JAK3 and Tyk2, and these kinases arecentral to the regulation of cytokine signaling in the immune system, aswell as more broadly in other tissues. The kinase activity of JAKs isdirected towards the JAKs themselves, the intracellular portion of thecytokine receptor, and several other substrates including the members ofthe STAT family of transcription factors. The STATs (STAT1 throughSTAT6) have specific and distinct effects on gene transcription innumerous cell types, including immune cells, and are critical inprocesses such as cell proliferation and differentiation. Due to thebroad role these kinases have in immunity and inflammation, numeroussmall molecule drugs have been developed to intervene in diseases whereJAK kinase signaling contributes to disease. Initially, these drugs weredeveloped for systemic administration for the prevention of organtransplant rejection. Subsequently they have been developed as potentialtherapies for hematologic malignancies, and autoimmune and inflammatorydiseases including rheumatoid arthritis, ulcerative colitis,inflammatory bowel disease, ankylosing spondylitis, psoriasis, atopicdermatitis, alopecia disorders, and vitiligo, to name a few. Morerecently, due to the hematologic, immunosuppressive and metabolictoxicities associated with systemic inhibition of the JAK kinases, localdelivery of these inhibitors as topical agents has been described. Theseinclude alopecia areata, atopic dermatitis, vitiligo, psoriasis,inflammatory bowel diseases, and dry eye, among others. This documentdescribes compounds that are expected to have excellent oral and topicalbioavailability and would be useful for systemic autoimmune disease, aswell as compounds designed to have limited stability and hence limitedsystemic exposure, therefore, be best suited for local (e.g., topical)drug delivery.

Signal transduction of cytokine receptors activated by cytokines hasbeen shown to occur through JAK kinases associated with receptorcytoplasmic domains. Receptor stimulation results in the activation ofthe JAKs and subsequent phosphorylation of the cytoplasmic domain of theassociated receptor chains. This creates an SH2-binding domain, whichserves to recruit the latent cytoplasmic transcription factors known asSTATs (Signal Transducer and Activator of Transcription). While bound tothe phosphorylated cytokine receptors, the STATs themselves becomephosphorylated on tyrosine residues—which leads to SH2-domain mediatedhomo- and hetero-dimer formation and translocation to the nucleus. Oncethere, these proteins induce the transcription of genes associated withactivation of the original cytokine receptor. This sequence of events(STAT protein phosphorylation in minutes, and STAT-induced genetranscription in hours) are both amenable to characterizing the cellularpotency of compounds and informing structure-activity relationships.

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, formulations, compositions, or methodologies described, asthese may vary. It is also to be understood that the terminology used inthe description is for the purpose of describing the particular versionsor embodiments only and is not intended to limit the scope ofembodiments herein which will be limited only by the appended claims.Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments of embodiments herein, the preferred methods, devices, andmaterials are now described. All publications mentioned herein areincorporated by reference in their entirety. Nothing herein is to beconstrued as an admission that embodiments herein are not entitled toantedate such disclosure by virtue of prior invention.

Definitions

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “JAK inhibitor” is a reference to one or more JAK inhibitors andequivalents thereof known to those skilled in the art, and so forth.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

In embodiments or claims where the term comprising is used as thetransition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of” or“consisting essentially of.”

As used herein, the term “consists of” or “consisting of” means that thecomposition, formulation or the method includes only the elements,steps, or ingredients specifically recited in the particular claimedembodiment or claim.

As used herein, the term “consisting essentially of” or “consistsessentially of” means that the composition, formulation or the methodincludes only the elements, steps or ingredients specifically recited inthe particular claimed embodiment or claim and may optionally includeadditional elements, steps or ingredients that do not materially affectthe basic and novel characteristics of the particular embodiment orclaim. For example, the only active ingredient(s) in the formulation ormethod that treats the specified condition (e.g., nutrient depletion) isthe specifically recited therapeutic(s) in the particular embodiment orclaim.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different from the other. For example,an embodiment wherein two groups combine to form a cycloalkyl ismutually exclusive with an embodiment in which one group is ethyl theother group is hydrogen. Similarly, an embodiment wherein one group isCH₂ is mutually exclusive with an embodiment wherein the same group isNH.

As used herein, the term “a derivative thereof” refers to a saltthereof, a pharmaceutically acceptable salt thereof, a free acid formthereof, a free base form thereof, a solvate thereof, a deuteratedderivative thereof, a hydrate thereof, an N-oxide thereof, a clathratethereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof,a geometric isomer thereof, a tautomer thereof, a mixture of tautomersthereof, an enantiomer thereof, a diastereomer thereof, a racematethereof, a mixture of stereoisomers thereof, an isotope thereof (e.g.,tritium, deuterium), or a combination thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a base or acid which is acceptable for administrationto a patient. The term “pharmaceutically acceptable salts” embracessalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. Such salts can be derived frompharmaceutically-acceptable inorganic or organic bases and frompharmaceutically-acceptable inorganic or organic acids.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” or “between n1 . . . and n2” is used, where n1 and n2 are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene (—CH═CH—). Examples ofsuitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,1,4-butadienyl and the like. Unless otherwise specified, the term“alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 8 carbon atoms. Alkyl groups may be optionally substituted as definedherein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl,octyl, noyl and the like. The term “alkylene,” as used herein, alone orin combination, refers to a saturated aliphatic group derived from astraight or branched chain saturated hydrocarbon attached at two or morepositions, such as methylene (—CH₂—). Unless otherwise specified, theterm “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C≡C—).

Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl,butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, andthe like. Unless otherwise specified, the term “alkynyl” may include“alkynylene” groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)NH(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently chosen from hydrogen, alkyl,acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,any of which may themselves be optionally substituted. Additionally, Rand R′ may combine to form heterocycloalkyl, either of which may beoptionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄═ derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group—with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, and tautomers, of the structuresdepicted. The term “compound” also includes the incorporation of allisotopes in any enrichment (e.g., tritium, deuterium) at any position inthe structures depicted.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “halocycloalkyl” as used herein, alone or in combination,refers to an cycloalkyl radical having the meaning as defined abovewherein one or more hydrogens are replaced with a halogen. Specificallyembraced are monohalocycloalkyl, dihalocycloalkyl and polyhalochaloalkylradicals. A monohaloalkyl radical, for one example, may have an iodo,bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl,chlorocyclobutyl, and chlorocyclopentyl.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or combinations thereof, fullysaturated or containing from 1 to 3 degrees of unsaturation, consistingof the stated number of carbon atoms and from one to three heteroatomschosen from N, O, and S, and wherein the N and S atoms may optionally beoxidized, and the N heteroatom may optionally be quaternized. Theheteroatom(s) may be placed at any interior position of the heteroalkylgroup. Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 5 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom chosenfrom N, O, and S. In certain embodiments, said heteroaryl will comprisefrom 1 to 4 heteroatoms as ring members. In further embodiments, saidheteroaryl will comprise from 1 to 2 heteroatoms as ring members. Incertain embodiments, said heteroaryl will comprise from 5 to 7 atoms.The term also embraces fused polycyclic groups wherein heterocyclicrings are fused with aryl rings, wherein heteroaryl rings are fused withother heteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated (but nonaromatic)monocyclic, bicyclic, or tricyclic heterocyclic group containing atleast one heteroatom as a ring member, wherein each said heteroatom maybe independently chosen from nitrogen, oxygen, and sulfur. In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms (i.e., C₁-C₆ alkyl).

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomschosen from N, O, and S, or 2) bicyclic heteroaryl, wherein each of thefused rings comprises five or six ring members, comprising between themone to four heteroatoms chosen from N, O, and S.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members(i.e., C₃-C₆ cycloalkyl). Lower cycloalkyls may be unsaturated. Examplesof lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomschosen from N, O, and S (i.e., C₃-C₆ heterocycloalkyl). Examples oflower heterocycloalkyls include pyrrolidinyl, piperidinyl, piperazinyl,and morpholinyl. Lower heterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently chosen from hydrogen andlower alkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

As used herein, an “N-oxide” is formed from the tertiary basic amines orimines present in the molecule, using a convenient oxidizing agent.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “substantially free” as used herein, alone or in combination,refers to a compound which is free from all other compounds within thelimits of detection as measured by any means including nuclear magneticresonance (NMR), gas chromatography/mass spectroscopy (GC/MS), or liquidchromatography/mass spectroscopy (LC/MS).

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO3H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition of amino.Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyland the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N3, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Wherestructurally feasible, two substituents may be joined together to form afused five-, six-, or seven-membered carbocyclic or heterocyclic ringconsisting of zero to three heteroatoms, for example formingmethylenedioxy or ethylenedioxy. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended. Additionally, different sets of optional substituents to aparticular moiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety chosen fromhydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl, any of which may be optionally substituted. Such R andR′ groups should be understood to be optionally substituted as definedherein. Whether an R group has a number designation or not, every Rgroup, including R, R′ and Rn where n=(1, 2, 3, . . . n), everysubstituent, and every term should be understood to be independent ofevery other in terms of selection from a group. Should any variable,substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.Those of skill in the art will further recognize that certain groups maybe attached to a parent molecule or may occupy a position in a chain ofelements from either end as written. For example, an unsymmetrical groupsuch as —C(O)N(R)— may be attached to the parent moiety at either thecarbon or the nitrogen.

Stereogenic centers exist in some of the compounds disclosed herein.These centers are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the stereogenic center. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, atropisomeric, racemicand epimeric forms, as well as d-isomers and l-isomers, and mixturesthereof. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain fixed stereogenic centers or by preparation of racemic mixturesof products followed by enantiomeric separation such as conversion to amixture of diastereomers followed by separation or recrystallization,chromatographic techniques, direct separation of enantiomers on chiralchromatographic columns, or any other appropriate method known in theart. Starting compounds of particular stereochemical configuration areeither commercially available or can be made and resolved by techniquesknown in the art. Additionally, the compounds disclosed herein may existas geometric isomers. The present invention includes all cis, trans,syn, anti, entgegen (E), and zusammen (Z) isomers as well as theappropriate mixtures thereof. Additionally, compounds may exist astautomers; all tautomeric isomers are provided by this invention.Additionally, the compounds disclosed herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single topical composition having afixed ratio of active ingredients or in multiple, separate topicalcompositions for each active ingredient. In addition, suchadministration also encompasses use of each type of therapeutic agent ina sequential manner. In either case, the treatment regimen will providebeneficial effects of the drug combination in treating the conditions ordisorders described herein.

“JAK1 and/or JAK3 inhibitor” is used herein to refer to a compound thatexhibits an IC₅₀ with respect to JAK1 and/or JAK3 activity of no morethan about 100 μM and more typically not more than about 50 μM, asmeasured in the JAK1 and JAK3 enzyme assays described generally herein.In some embodiments, the compounds will exhibit an IC₅₀ with respect toJAK1 and/or JAK3 of about 1 μM to about 50 μM. IC₅₀ is thatconcentration of inhibitor which reduces the activity of an enzyme(e.g., JAK1 and/or JAK3) to half-maximal level. Certain compoundsdisclosed herein have been discovered to exhibit inhibition against JAK1and/or JAK3. In some embodiments, the compounds will exhibit an IC₅₀with respect to JAK1 and/or JAK3 of no more than about 300 nM. In someembodiments, the compounds will exhibit an IC₅₀ with respect to JAK1and/or JAK3 of no more than about 1 nM. In certain embodiments,compounds will exhibit an IC₅₀ with respect to JAK1 and/or JAK3 of nomore than about 50 μM; in further embodiments, compounds will exhibit anIC₅₀ with respect to JAK1 and/or JAK3 of no more than about 10 μM; inyet further embodiments, compounds will exhibit an IC₅₀ with respect toJAK1 and/or JAK3 of not more than about 5 μM; in yet furtherembodiments, compounds will exhibit an IC₅₀ with respect to JAK1 and/orJAK3 of not more than about 1 μM, as measured in the JAK1 and/or JAK3assay described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In part, embodiments of the present invention are directedto the treatment of JAK1 and/or JAK3-mediated diseases.

The term “therapeutically acceptable” refers to those compounds, or aderivative thereof, which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. Treatment may also be preemptive in nature, i.e.,it may include prevention of disease. Prevention of a disease mayinvolve complete protection from disease, for example as in the case ofprevention of infection with a pathogen, or may involve prevention ofdisease progression. For example, prevention of a disease may not meancomplete foreclosure of any effect related to the diseases at any level,but instead may mean prevention of the symptoms of a disease to aclinically significant or detectable level. Prevention of diseases mayalso mean prevention of progression of a disease to a later stage of thedisease.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a patient whereby the therapeutic positivelyimpacts the tissue to which it is targeted. Thus, as used herein, theterm “administering”, when used in conjunction with a compound ofembodiments herein, can include, but is not limited to, providing thecompound into or onto the target tissue; providing the compoundsystemically to a patient by, e.g., intravenous injection whereby thetherapeutic reaches the target tissue; providing the compound in theform of the encoding sequence thereof to the target tissue (e.g., byso-called gene-therapy techniques). “Administering” a composition may beaccomplished by injection, topically, orally, or by any of these methodsin combination with other known techniques.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug.

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Novel compounds and pharmaceutical compositions, certain of which havebeen found to inhibit JAK1 and/or JAK3 kinase have been discovered,together with methods of synthesizing and using the compounds including,without limitation, methods for the treatment of JAK1 and/or JAK3mediated diseases in a patient by topically administering the compounds.

Compounds of the present invention may be selective amongst the JAK1and/or JAK3 isoforms in various ways. For example, compounds describedherein may be selective for JAK1 and/or JAK3 over other isoforms, suchas JAK2 and Tyk-2, be a pan-inhibitor of all the isoforms, or beselective for only one isoform. In certain embodiments, compounds of thepresent invention are selective for JAK1 and/or JAK3 over otherisoforms. In some embodiments, the compounds disclosed herein areselective for JAK1 and/or JAK3 over JAK2 and Tyk-2. Selectivity may bedetermined using enzyme assays, cellular assays or both. In someembodiments, the compounds disclosed herein are at least about 10×selective for JAK1 and/or JAK3 receptors over JAK2 receptor. In someembodiments, the compounds disclosed herein are at least about 10×selective for JAK1 and/or JAK3 receptors over Tyk-2 receptor.

Compounds

Embodiments herein are directed to compounds and pharmaceuticalcompositions, certain of which have been found to inhibit JAK1 and/orJAK3 Kinase, together with methods of synthesizing and using thecompounds. Some embodiments include methods for the treatment ofdiseases in a patient by topically administering the compounds ofembodiments herein.

Certain compounds disclosed herein may possess useful JAK1 and/or JAK3inhibiting activity and may be used in the treatment or prophylaxis of adisease or condition in which JAK1 and/or JAK3 plays an active role.Thus, embodiments are also directed to pharmaceutical compositionscomprising one or more compounds disclosed herein together with apharmaceutically acceptable carrier, as well as methods of making andusing the compounds and compositions. Certain embodiments are directedto methods for inhibiting JAK1 and/or JAK3. Other embodiments aredirected to methods for treating a JAK1 and/or JAK3-mediated disorder ina patient in need of such treatment, comprising administering to saidpatient a therapeutically effective amount of a compound or compositionaccording to the present invention. Also provided is the use of certaincompounds disclosed herein in the manufacture of a medicament for thetreatment of a disease or condition ameliorated by the inhibition ofJAK1 and/or JAK3.

Also provided are embodiments wherein any embodiment herein may becombined with any one or more of the other embodiments, unless otherwisestated and provided the combination is not mutually exclusive.

Also provided is a compound chosen from the Examples disclosed herein.The compounds of embodiments herein may also refer to a salt thereof, anester thereof, a free acid form thereof, a free base form thereof, asolvate thereof, a deuterated derivative thereof, a hydrate thereof, anN-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorphthereof, a stereoisomer thereof, an enantiomer thereof, a diastereomerthereof, a racemate thereof, a mixture of stereoisomers thereof, atautomer thereof, a mixture of tautomers thereof, or a combination ofthe foregoing of the compounds of embodiments herein.

Compounds described herein may contain a stereogenic center and may bechiral and thus exist as enantiomers. Where the compounds according toembodiments herein possess two or more stereogenic centers, they mayadditionally exist as diastereomers. Embodiments herein includes allpossible stereoisomers as substantially pure resolved enantiomers,racemic mixtures thereof, as well as mixtures of diastereomers. In someembodiments, the formulas are shown without a definitive stereochemistryat certain positions. Embodiments herein includes all stereoisomers ofsuch formulas and pharmaceutically acceptable salts thereof.Diastereoisomeric pairs of stereoisomers may be separated by, forexample, fractional crystallization from a suitable solvent, and pairsof enantiomers thus obtained may be separated into individualstereoisomers by conventional means, for example by the use of anoptically active acid or base as a resolving agent or on a chiral HPLCcolumn. Further, any enantiomer or diastereomer of a compound of thegeneral formula may be obtained by stereospecific or stereoselectivesynthesis using optically pure or enantioenriched starting materials orreagents of known configuration. The scope of embodiments herein asdescribed and claimed encompasses the racemic forms of the compounds aswell as the individual enantiomers, diastereomers, andstereoisomer-enriched mixtures.

Conventional techniques for the preparation/isolation of individualenantiomers include stereoselective synthesis from a suitableenantioenriched or optically pure precursors or resolution of theracemate using, for example, chiral high pressure liquid chromatography(HPLC). Alternatively, the racemate (or a racemic precursor) may bereacted with a suitable optically active compound, for example, analcohol, or, in the case where the compound contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to one skilled in the art. Chiral compounds ofembodiments herein (and chiral precursors thereof) may be obtained inenantiomerically-enriched form using chromatography, typically HPLC, onan asymmetric resin with a mobile phase consisting of a hydrocarbon,typically heptane or hexane, containing from 0 to 50% isopropanol,typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically0.1% diethylamine. Concentration of the eluate affords the enrichedmixture. Stereoisomer conglomerates may be separated by conventionaltechniques known to those skilled in the art. See, e.g.,“Stereochemistry of Organic Compounds” by Ernest L. Eliel (Wiley, NewYork, 1994).

Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. Oki (Oki, M; Topics inStereochemistry 1983, 1) defined atropisomers as conformers thatinterconvert with a half-life of more than 1000 seconds at a giventemperature. The scope of embodiments herein as described and claimedencompasses the racemic forms of the compounds as well as the individualatropisomers (an atropisomer “substantially free” of its correspondingatropisomer) and stereoisomer-enriched mixtures, i.e., mixtures ofatropisomers.

Separation of atropisomers is possibly by chiral resolution methods suchas selective crystallization. In an atropo-enantioselective oratroposelective synthesis one atropisomer is formed at the expense ofthe other. Atroposelective synthesis may be carried out by use of chiralauxiliaries like a Corey-Bakshi-Shibata (CBS) catalyst (asymmetriccatalyst derived from proline) in the total synthesis of knipholone orby approaches based on thermodynamic equilibration when an isomerizationreaction favors one atropisomer over the other.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of embodiments herein may be prepared from an inorganic acidor an organic acid. All of these salts may be prepared by conventionalmeans from the corresponding compound of embodiments herein by treating,for example, the compound with the appropriate acid or base.

Pharmaceutically acceptable acids include both inorganic acids, forexample hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,sulfuric, phosphoric and diphosphoric acid; and organic acids, forexample formic, acetic, trifluoroacetic, propionic, succinic, glycolic,embonic (pamoic), methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic,sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,β-hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric,gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic,oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic(1-hydroxy-2-naphthoic acid), napadisilic (1,5-naphthalenedisulfonicacid) and the like.

Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary and tertiary amines, including alkyl amines,arylalkyl amines, heterocyclyl amines, cyclic amines,naturally-occurring amines and the like, such as arginine, betaine,caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like.

Other preferred salts according to embodiments herein are quaternaryammonium compounds wherein an equivalent of an anion (X—) is associatedwith the positive charge of the N atom. X— may be an anion of variousmineral acids such as, for example, chloride, bromide, iodide, sulphate,nitrate, phosphate, or an anion of an organic acid such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, trifluoroacetate, methanesulphonate andp-toluenesulphonate. X— is preferably an anion selected from chloride,bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinateor trifluoroacetate. More preferably X— is chloride, bromide,trifluoroacetate or methanesulphonate.

As used herein, an N-oxide is formed from the tertiary basic amines orimines present in the molecule, using a convenient oxidizing agent.

The compounds of embodiments herein may exist in both unsolvated andsolvated forms. The term solvate is used herein to describe a molecularcomplex comprising a compound of embodiments herein and an amount of oneor more pharmaceutically acceptable solvent molecules. The term hydrateis employed when said solvent is water. Examples of solvate formsinclude, but are not limited to, compounds of embodiments herein inassociation with water, acetone, dichloromethane, 2-propanol, ethanol,methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid,ethanolamine, or mixtures thereof. It is specifically contemplated thatin embodiments herein one solvent molecule can be associated with onemolecule of the compounds of embodiments herein, such as a hydrate.

Furthermore, it is specifically contemplated that in embodiments herein,more than one solvent molecule may be associated with one molecule ofthe compounds of embodiments herein, such as a dihydrate. Additionally,it is specifically contemplated that in embodiments herein less than onesolvent molecule may be associated with one molecule of the compounds ofembodiments herein, such as a hemihydrate. Furthermore, solvates ofembodiments herein are contemplated as solvates of compounds ofembodiments herein that retain the biological effectiveness of thenon-solvate form of the compounds.

Embodiments herein also include isotopically-labeled compounds ofembodiments herein, wherein one or more atoms is replaced by an atomhaving the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes suitable for inclusion in the compounds ofembodiments herein include isotopes of hydrogen, such as ²H and ³H,carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³¹Cl, fluorine, suchas ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N,oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur,such as ³⁵S. Certain isotopically-labeled compounds of embodimentsherein, for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, ³H, and carbon-14, ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection. Substitution with heavier isotopes such asdeuterium, 2H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements, and hence may be preferred in somecircumstances. Substitution with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of embodiments herein can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Preferred isotopically-labeled compounds include deuterated derivativesof the compounds of embodiments herein. As used herein, the termdeuterated derivative embraces compounds of embodiments herein where ina particular position at least one hydrogen atom is replaced bydeuterium. Deuterium (D or ²H) is a stable isotope of hydrogen which ispresent at a natural abundance of 0.015 molar %.

Hydrogen deuterium exchange (deuterium incorporation) is a chemicalreaction in which a covalently bonded hydrogen atom is replaced by adeuterium atom. Said exchange (incorporation) reaction can be total orpartial.

Typically, a deuterated derivative of a compound of embodiments hereinhas an isotopic enrichment factor (ratio between the isotopic abundanceand the natural abundance of that isotope, i.e. the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen) for each deuterium present at a site designated as apotential site of deuteration on the compound of at least 3500 (52.5%deuterium incorporation).

In some embodiments, the isotopic enrichment factor is at least 5000(75% deuterium). In some embodiments, the isotopic enrichment factor isat least 6333.3 (95% deuterium incorporation). In some embodiments, theisotopic enrichment factor is at least 6633.3 (99.5% deuteriumincorporation). It is understood that the isotopic enrichment factor ofeach deuterium present at a site designated as a site of deuteration isindependent from the other deuteration sites.

The isotopic enrichment factor can be determined using conventionalanalytical methods known to one of ordinary skilled in the art,including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

Prodrugs of the compounds described herein are also within the scope ofembodiments herein. Thus, certain derivatives of the compounds ofembodiments herein, which derivatives may have little or nopharmacological activity themselves, when administered into or onto thebody may be converted into compounds of embodiments herein having thedesired activity, for example, by hydrolytic cleavage. Such derivativesare referred to as ‘prodrugs’. Further information on the use ofprodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14,ACS Symposium Series (T. Higuchi and W. Stella) and BioreversibleCarriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association).

Prodrugs in accordance with embodiments herein can, for example, beproduced by replacing appropriate functionalities present in thecompounds of embodiments herein with certain moieties known to thoseskilled in the art as ‘pro-moieties’ as described, for example, inDesign of Prodrugs by H. Bundgaard (Elsevier, 1985).

In the case of compounds of embodiments herein that are solids, it isunderstood by those skilled in the art that the inventive compounds andsalts may exist in different crystalline or polymorphic forms, or in anamorphous form, all of which are intended to be within the scope ofembodiments herein.

The compounds disclosed herein can exist as and therefore include allstereoisomers, conformational isomers and mixtures thereof in allproportions as well as isotopic forms such as deuterated compounds.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

In certain embodiments, compounds have structural Formula (I):

-   -   wherein:        -   R₁ is selected from —CO₂R₅, —C₁-C₅alkyl-CO₂R₅,            —C₃-C₆-cycloalkyl-CO₂R₅, —NHCO₂R₅, —N(C₁-C₅ alkyl)-CO₂R₅,            —O—CO₂R₅, or —C₁-C₅alkyl-O—CO₂R₅;        -   R₂ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring A is substituted at one or more carbons with one, two,            or three R₃ substituents wherein each R₃ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃ groups on the same or different carbon atoms of the ring        A may be optionally joined to form a spirocyclic or bicyclic        ring system with ring A;        -   R₄ is selected from —C(O)—R₆, —CH₂R₆, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇R₈,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;        -   R₅ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein            the alkyl or cycloalkyl groups may be optionally substituted            by one or more groups selected from halogen, —OH, or            —O—C₁-C₅alkyl;        -   R₆ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,            —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇R₈, —O-aryl, —O-heteroaryl,            aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or            heteroaryl groups can be optionally substituted by one or            more groups selected from halogen, —CN, alkyne, —OH,            trifluoromethyl, —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;        -   R₇ and R₈ are independently selected from H, —C₁-C₅ alkyl,            —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups            may be optionally substituted by one or more groups selected            from halogen, —OH, or —CN;            -   R₇ and R₈ may be optionally joined to form a ring to                form a heterocycle such as piperidine, pyrrolidine, or                with another heteroatom to form a ring such as                morpholine.

In certain embodiments, compounds have structural Formula (Ia):

-   -   wherein:        -   R₂₁ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring B is substituted at one or more carbons with one, two,            or three R₃₁ substituents wherein each R₃₁ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₁ groups on the same or different carbon atoms of the ring        B may be optionally joined to form a spirocyclic or bicyclic        ring system with ring B;        -   R₄₁ is selected from —C(O)—R₆₁, —CH₂R₆₁, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇₁R₈₁,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₁ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₁ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₁R₈₁, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₁ and R₈₁ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;        -   R₇₁ and R₁₈ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (Ib):

-   -   wherein:        -   R₂₂ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;        -   n is 0, 1 or 2;        -   Ring C is substituted at one or more carbons with one, two,            or three R₃₂ substituents wherein each R₃₂ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₂ groups on the same or different carbon atoms of the ring        C may be optionally joined to form a spirocyclic or bicyclic        ring system with ring C;        -   R₄₂ is selected from —C(O)—R₆₂, —CH₂R₆₂, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH—CHCH₃, —C(O)—CH═CHCH₂NR₇₂R₈₂,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₂ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₂ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₃R₈₃, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₂ and R₈₂ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen. —OH, or —CN;        -   R₇₂ and R₈₂ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (Ic):

-   -   wherein:        -   R₂₃ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring D is substituted at one or more carbons with one, two,            or three R₃₃ substituents wherein each R₃₃ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅ alkyl;    -   Two R₃₃ groups on the same or different carbon atoms of the ring        D may be optionally joined to form a spirocyclic or bicyclic        ring system with ring D;        -   R₄₃ is selected from —C(O)—R₆₃, —CH₂R₆₃, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇₃R₈₃,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₃ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₃ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₃R₈₃, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₃ and R₈₃ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;        -   R₇₃ and R₈₃ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (Id):

-   -   wherein:        -   R₂₄ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring E is substituted at one or more carbons with one, two,            or three R₃₄ substituents wherein each R₃₄ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₄ groups on the same or different carbon atoms of the ring        E may be optionally joined to form a spirocyclic or bicyclic        ring system with ring E;        -   R₄₄ is selected from —C(O)—R₆₄, —CH₂R₆₄, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇₄R₈₄,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₄ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₄ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₄R₈₄, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₄ and R₈₄ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;        -   R₇₄ and R₈₄ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (Ie):

-   -   wherein:        -   R₂₅ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring F is substituted at one or more carbons with one, two,            or three R₃₅ substituents wherein each R₃₅ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₅ groups on the same or different carbon atoms of the ring        F may be optionally joined to form a spirocyclic or bicyclic        ring system with ring F;        -   R₄₅ is selected from —C(O)—R₆₅, —CH₂R₆₅, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇₅R₈₅,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₅ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₅ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₅R₈₅, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₅ and R₈₅ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;        -   R₇₅ and R₈₅ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (If):

-   -   wherein:        -   R₂₆ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring G is substituted at one or more carbons with one, two,            or three R₃₆ substituents wherein each R₃₆ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₆ groups on the same or different carbon atoms of the ring        G may be optionally joined to form a spirocyclic or bicyclic        ring system with ring G;        -   R₄₆ is selected from —C(O)—R₆₆, —CH₂R₆₆, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇₆R₈₆,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₆ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₆ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₆R₈₆, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₆ and R₈₆ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;        -   R₇₆ and R₈₆ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (Ig):

-   -   wherein:        -   R₂₇ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring H is substituted at one or more carbons with one, two,            or three R₃₇ substituents wherein each R₃₇ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₇ groups on the same or different carbon atoms of the ring        H may be optionally joined to form a spirocyclic or bicyclic        ring system with ring H;        -   R₄₇ is selected from —C(O)—R₆₇, —CH₂R₆₇, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇₇R₈₇,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₇ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₇ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₇R₈₇, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₇ and R₈₇ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;        -   R₇₇ and R₈₇ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (II):

-   -   wherein:    -   R₁₀ is selected from —CO₂R₅₀, —C₁-C₅-alkyl-CO₂R₅₀,        —C₃-C₆-cycloalkyl-CO₂R₅₀, —NHCO₂R₅₀, —N(C₁-C₅ alkyl)-CO₂R₅₀,        —O—CO₂R₅₀, or —C₁-C₅alkyl-O—CO₂R₅₀;    -   R₂₀ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring I is substituted at one or more carbons with one, two, or        three R₃₀ substituents wherein each R₃₀ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀C(O)—CH═CH₂, —NR₇₀C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀C(O)—CH═CHCH₃, or —NR₇₀C(O)—CH═CHCH₂NR₈₀R₉₀ wherein each        alkyl or cycloalkyl group is optionally substituted with one or        more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or        —O—C₁-C₅alkyl;    -   Two R₃₀ groups on the same carbon atom or two or three R₃₀        groups on different carbon atoms of ring I may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring I such as adamantyl;    -   R₄₀ is selected from H, —OH, —C(O)—R₆₀, —OR₆₀, —O—C(O)—R₆₀,        —NR₇₀—C(O)—R₆₀, —C₁-C₄alkyl-C(O)—R₆₀, —SO₂—R₆₀₁, —SO₂—NR₈₀R₉₀,        —C₁-C₄alkyl-SO₂—R₆₀, or —C₁-C₄alkyl-SO₂NR₈₀R₉₀;    -   R₅₀ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀ and R₉₀ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, or —C₃-C₆cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and        -   R₈₀ and R₉₀ may be optionally joined to form a ring to form            a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (IIa):

-   -   wherein:    -   R₂₀₁ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring J is substituted at one or more carbons with one, two, or        three R₃₀₁ substituents wherein each R₃₀₁ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₁C(O)—CH═CH₂, —NR₇₀₁C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀₁C(O)—CH═CHCH₃, or —NR₇₀₁C(O)—CH═CHCH₂NR₈₀₁R₉₀₁ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₁ groups on the same carbon atom or two or three R₃₀₁        groups on different carbon atoms of ring J may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring J such as adamantyl;    -   R₄₀₁ is selected from H, —OH, —C(O)—R₆₀₁, —OR₆₀₁, —O—C(O)—R₆₀₁,        —NR₇₀₁—C(O)—R₆₀₁, —C₁-C₄alkyl-C(O)—R₆₀₁, —SO₂—R₆₀₁,        —SO₂—NR₈₀₁R₉₀₁, —C₁-C₄alkyl-SO₂—R₆₀₁, or        —C₁-C₄alkyl-SO₂NR₈₀₁R₉₀₁;    -   R₅₀₁ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₁ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₁ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₁ and R₉₀₁ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, or —C₃-C₆cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN; or        -   R₈₀₁ and R₉₀₁ may be optionally joined to form a ring to            form a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (IIb):

-   -   wherein:    -   R₂₀₂ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring K is substituted at one or more carbons with one, two, or        three R₃₀₂ substituents wherein each R₃₀₂ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₂C(O)—CH═CH₂, —NR₇₀₂C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀₂C(O)—CH═CHCH₃, or —NR₇₀₂C(O)—CH═CHCH₂NR₈₀₂R₉₀₂ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₂ groups on the same carbon atom or two or three R₃₀₂        groups on different carbon atoms of ring K may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring K such as adamantyl;    -   R₄₀₂ is selected from H, —OH, —C(O)—R₆₀₂, —OR₆₀₂, —O—C(O)—R₆₀₂,        —NR₇₀₂—C(O)—R₆₀₂, —C₁-C₄alkyl-C(O)—R₆₀₂, —SO₂—R₆₀₂,        —SO₂—NR₈₀₂R₉₀₂, —C₁-C₄alkyl-SO₂—R₆₀₂, or        —C₁-C₄alkyl-SO₂NR₈₀₂R₉₀₂;    -   R₅₀₂ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₂ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₂ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₂ and R₉₀₂ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, —C₃-C₆cycloalkyl wherein the alkyl groups may be        optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and        -   R₈₀₂ and R₉₀₂ may be optionally joined to form a ring to            form a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (IIc):

-   -   wherein:    -   R₂₀₃ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring L is substituted at one or more carbons with one, two, or        three R₃₀₃ substituents wherein each R₃₀₃ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₃C(O)—CH═CH₂, —NR₇₀₃C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀₃C(O)—CH═CHCH₃, or —NR₇₀₃C(O)—CH═CHCH₂NR₈₀₃R₉₀₃ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₃ groups on the same carbon atom or two or three R₃₀₃        groups on different carbon atoms of ring L may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring L such as adamantyl;    -   R₄₀₃ is selected from H, —OH, —C(O)—R₆₀₃, —OR₆₀₃, —O—C(O)—R₆₀₃,        —NR₇₀₃—C(O)—R₆₀₃, —C₁-C₄alkyl-C(O)—R₆₀₃, —SO₂—R₆₀₃,        —SO₂—NR₈₀₃R₉₀₃, —C₁-C₄alkyl-SO₂—R₆₀₃, or        —C₁-C₄alkyl-SO₂NR₈₀₃R₉₀₃;    -   R₅₀₃ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₃ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₃ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₃ and R₉₀₃ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, —C₃-C₆cycloalkyl wherein the alkyl groups may be        optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and R₈₀₃ and R₉₀₃ may be optionally joined        to form a ring to form a heterocycle such as piperidine,        pyrrolidine, or with another heteroatom to form a ring such as        morpholine.

In certain embodiments, compounds have structural Formula (IId):

-   -   wherein:    -   R₂₀₄ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring M is substituted at one or more carbons with one, two, or        three R₃₀₄ substituents wherein each R₃₀₄ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₄C(O)—CH═CH₂, —NR₇₀₄C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀₄C(O)—CH═CHCH₃, or —NR₇₀₄C(O)—CH═CHCH₂NR₈₀₄R₉₀₄ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₄ groups on the same carbon atom or two or three R₃₀₄        groups on different carbon atoms of ring M may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring M such as adamantyl;    -   R₄₀₄ is selected from H, —OH, —C(O)—R₆₀₄, —OR₆₀₄, —O—C(O)—R₆₀₄,        —NR₇₀₄—C(O)—R₆₀₄, —C₁-C₄alkyl-C(O)—R₆₀₄, —SO₂—R₆₀₄,        —SO₂—NR₈₀₄R₉₀₄, —C₁-C₄alkyl-SO₂—R₆₀₄, or        —C₁-C₄alkyl-SO₂NR₈₀₄R₉₀₄;    -   R₅₀₄ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₄ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl where the alkyl or cycloalkyl groups        can be optionally substituted by one or more groups selected        from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₄ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₄ and R₉₀₄ are independently selected from H, —C₁-C₅alkyl, or        —C₁-C₅alkoxy, —C₃-C₆cycloalkyl wherein the alkyl groups may be        optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and        -   R₈₀₄ and R₉₀₄ may be optionally joined to form a ring to            form a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (IIe):

-   -   wherein:    -   R₂₀₅ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl,        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring N is substituted at one or more carbons with one, two, or        three R₃₀₅ substituents wherein each R₃₀₅ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₅C(O)—CH═CH₂, —NR₇₀₅C(O)—C(CH₂OCH₃)CH₂,        —NR₇₀₅C(O)—CH═CHCH₃, or —NR₇₀₅C(O)—CH═CHCH₂NR₈₀₅R₉₀₅ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₅ groups on the same carbon atom or two or three R₃₀₅        groups on different carbon atoms of ring N may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring N such as adamantyl;    -   R₄₀₅ is selected from H, —OH, —C(O)—R₆₀₅, —OR₆₀₅, —O—C(O)—R₆₀₅,        —NR₇₀₅—C(O)—R₆₀₅, —C₁-C₄alkyl-C(O)—R₆₀₅, —SO₂—R₆₀₅,        —SO₂—NR₈₀₅R₉₀₅, —C₁-C₄alkyl-SO₂—R₆₀₅, or        —C₁-C₄alkyl-SO₂NR₈₀₅R₉₀₅;    -   R₅₀₅ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₅ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₅ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₅ and R₉₀₅ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, —C₃-C₆cycloalkyl wherein the alkyl groups may be        optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and        -   R₈₀₅ and R₉₀₅ may be optionally joined to form a ring to            form a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (IIf):

-   -   wherein:    -   R₂₀₆ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring O is substituted at one or more carbons with one, two, or        three R₃₀₆ substituents wherein each R₃₀₆ group is independently        selected from H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₆C(O)—CH═CH₂, —NR₇₀₆C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀₆C(O)—CH═CHCH₃, or —NR₇₀₆C(O)—CH═CHCH₂NR₈₀₆R₉₀₆ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₆ groups on the same carbon atom or two or three R₃₀₆        groups on different carbon atoms of ring O may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring O such as adamantyl;    -   R₄₀₆ is selected from H, —OH, —C(O)—R₆₀₆, —OR₆₀, —O—C(O)—R₆₀₆,        —NR₇₀₆—C(O)—R₆₀₆, —C₁-C₄alkyl-C(O)—R₆₀₆, —SO₂—R₆₀₆,        —SO₂—NR₈₀₆R₉₀₆, —C₁-C₄alkyl-SO₂—R₆₀₆, or        —C₁-C₄alkyl-SO₂NR₈₀₆R₉₀₆;    -   R₅₀₆ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₆ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₆ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₆ and R₉₀₆ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, —C₃-C₆cycloalkyl wherein the alkyl groups may be        optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and        -   R₈₀₆ and R₉₀₆ may be optionally joined to form a ring to            form a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (IIg):

-   -   wherein:    -   R₂₀₇ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring P is substituted at one or more carbons with one, two, or        three R₃₀₇ substituents wherein each R₃₀₇ group is independently        selected from H, halogen, —C₁-C₅alkyl, —C₃-C₆cycloalkyl, —OH,        —O—C₁-C₅alkyl, —NR₇₀₇C(O)—CH═CH₂, —NR₇₀₇C(O)—C(CH₂OCH₃)═CH₂,        —NR₇₀₇C(O)—CH═CHCH₃, or —NR₇₀₇C(O)—CH═CHCH₂NR₈₀₇R₉₀₇ wherein        each alkyl or cycloalkyl group is optionally substituted with        one or more groups selected from: halogen, —OH,        —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl;    -   Two R₃₀₇ groups on the same carbon atom or two or three R₃₀₇        groups on different carbon atoms of ring P may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring P such as adamantyl;    -   R₄₀₇ is selected from H, —OH, —C(O)—R₆₀₇, —OR₆₀₇, —O—C(O)—R₆₀₇,        —NR₇₀₇—C(O)—R₆₀₇, —C₁-C₄alkyl-C(O)—R₆₀₇, —SO₂—R₆₀₇,        —SO₂—NR₈₀₇R₉₀₇, —C₁-C₄alkyl-SO₂—R₆₀₇, or        —C₁-C₄alkyl-SO₂NR₈₀₇R₉₀₇;    -   R₅₀₇ is selected from —C₁-C₅alkyl, or —C₃-C₅cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₇ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₅cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₇ is selected from H, —C₁-C₅alkyl or —C₃-C₅cycloalkyl;    -   R₈₀₇ and R₉₀₇ are independently selected from H, —C₁-C₅alkyl,        —C₁-C₅alkoxy, —C₃-C₆cycloalkyl wherein the alkyl groups may be        optionally substituted by one or more groups selected from        halogen, —OH, or —CN; and        -   R₈₀₇ and R₉₀₇ may be optionally joined to form a ring to            form a heterocycle such as piperidine, pyrrolidine, or with            another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds have structural Formula (III):

-   -   wherein:        -   R₁₀₀₀ is selected from —CO₂R₅₀₀₀, —C₁-C₅alkyl-CO₂R₅₀₀₀,            —C₃-C₆-cycloalkyl-CO₂R₅₀₀₀, —NHCO₂R₅₀₀₀, —N(C₁-C₅            alkyl)-CO₂R₅₀₀₀, —O—CO₂R₅₀₀₀, or —C₁-C₅alkyl-O—CO₂R₅₀₀₀;        -   R₂₀₀₀ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or            —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl            groups are optionally substituted with one or more groups            selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;        -   Ring Q is substituted at one or more carbons with one, two,            or three R₃ substituents wherein each R₃₀₀₀ group is            independently selected from H, halogen, —C₁-C₄alkyl,            —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl            or cycloalkyl group is optionally substituted with one or            more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy,            or —O—C₁-C₅alkyl;    -   Two R₃₀₀₀ groups on the same or different carbon atoms of the        ring Q may be optionally joined to form a spirocyclic or        bicyclic ring system with ring Q;        -   R₄₀₀₀ is selected from —C(O)—R₆₀₀₀, —CH₂R₆₀₀₀, —C(O)—CH═CH₂,            —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇R₈,            —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the            alkyl or cycloalkyl groups may be optionally substituted            with one or more groups selected from —OH, halogen, alkyne,            or —CN;    -   R₅₀₀₀ is selected from H, —C₁-C₅alkyl, and —C₃-C₆cycloalkyl        wherein the alkyl or cycloalkyl groups may be optionally        substituted by one or more groups selected from halogen, —OH,        —C₃-C₆cycloalkyl, or —O—C₁-C₅alkyl;    -   R₆₀₀₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₀₀₀R₈₀₀₀, —O-aryl,        —O-heteroaryl, aryl, or heteroaryl wherein the alkyl,        cycloalkyl, aryl or heteroaryl groups can be optionally        substituted by one or more groups selected from halogen, —CN,        alkyne, —OH, trifluoromethyl, —O—C₁-C₅alkyl, or        —O—C₃-C₆cycloalkyl;    -   R₇₀₀₀ and R₈₀₀₀ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;    -   R₇₀₀₀ and R₈₀₀₀ may be optionally joined to form a ring to form        a heterocycle such as piperidine, pyrrolidine, or with another        heteroatom to form a ring such as morpholine.

In certain embodiments of the present invention, compounds havestructural Formula (IV):

-   -   wherein:    -   R₁₀₀₀₀ is selected from —CO₂R₅₀₀₀₀, —C₁-C₅-alkyl-CO₂R₅₀₀₀₀,        —C₃-C₆-cycloalkyl-CO₂R₅₀₀₀₀, —NHCO₂R₅₀₀₀₀, —N(C₁-C₅        alkyl)-CO₂R₅₀₀₀₀, —O—CO₂R₅₀₀₀₀, or —C₁-C₅alkyl-O—CO₂R₅₀₀₀₀;    -   R₂₀₀₀₀ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0 or 1;    -   Ring S is substituted at one or more carbons with one, two, or        three R₃₀ substituents wherein each R₃₀₀₀₀ group is        independently selected from H, halogen, —C₁-C₄alkyl,        —C₃-C₆cycloalkyl, —OH, —O—C₁-C₅alkyl, —NR₇₀₀₀₀C(O)—CH═CH₂,        —NR₇₀₀₀₀C(O)—C(CH₂OCH₃)═CH₂, —NR₇₀₀₀₀C(O)—CH═CHCH₃, or        —NR₇₀₀₀₀C(O)—CH═CHCH₂NR₈₀₀₀₀R₉₀₀₀₀ wherein each alkyl or        cycloalkyl group is optionally substituted with one or more        groups selected from: halogen, —CN, —OH, —C₁-C₅alkylalkoxy, or        —O—C₁-C₅alkyl;    -   Two R₃₀₀₀₀ groups on the same carbon atom or two or three R₃₀        groups on different carbon atoms of ring S may be optionally        joined to form a spirocyclic, bicyclic, or tricyclic ring system        with ring S such as adamantyl;    -   R₄₀₀₀₀ is selected from H, —OH, —C(O)—R₆₀₀₀₀, —OR₆₀₀₀₀,        —O—C(O)—R₆₀₀₀₀, —NR₇₀₀₀₀—C(O)—R₆₀₀₀₀, —C₁-C₄alkyl-C(O)—R₆₀₀₀₀,        —SO₂—R₆₀₀₀₀, —SO₂—NR₈₀₀₀₀R₉₀₀₀₀, —C₁-C₄alkyl-SO₂—R₆₀₀₀₀, or        —C₁-C₄alkyl-SO₂NR₈₀₀₀₀R₉₀₀₀₀;    -   R₅₀₀₀₀ is selected from H, —C₁-C₅alkyl, and —C₃-C₆cycloalkyl        wherein the alkyl or cycloalkyl groups may be optionally        substituted by one or more groups selected from halogen, —OH,        —C₃-C₆cycloalkyl, or —O—C₁-C₅alkyl;    -   R₆₀₀₀₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl or        —C₁-C₅alkyl-C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl        groups can be optionally substituted by one or more groups        selected from halogen, —CN, alkyne, —OH, or —O—C₁-C₅alkyl;    -   R₇₀₀₀₀ is selected from H, —C₁-C₅alkyl or —C₃-C₆cycloalkyl;    -   R₈₀₀₀₀ and R₉₀₀₀₀ are independently selected from H,        —C₁-C₅alkyl, —C₁-C₅alkoxy, or —C₃-C₆cycloalkyl wherein the alkyl        groups may be optionally substituted by one or more groups        selected from halogen, —OH, or —CN; and    -   R₈₀₀₀₀ and R₉₀₀₀₀ may be optionally joined to form a ring to        form a heterocycle such as piperidine, pyrrolidine, or with        another heteroatom to form a ring such as morpholine.

In certain embodiments, compounds of structural Formula (II), Formula(IIa) or Formula (IV) are not the following:

The invention is further illustrated by the following examples ofcompounds of Formula (I)

Example # Structure Name 1

ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2

methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrollo[2,3-b]pyridine-5-carboxylate 3

ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 4

methoxymethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 5

isopropyl 4-(((3S,4S)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 6

ethyl 4-(((3S,4S)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 7

isopropyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 8

ethyl 4-(((3R,4R)-1-(cyclopentanecarbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 9

methyl 4-(((3R,4R)-1-(cyclopentanecarbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 10

methyl 4-(methyl((3R,4R)-4-methyl-1-(pyrrolidine-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate11

ethyl 4-(methyl((3R,4R)-4-methyl-1-(pyrrolidine-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate12

isopropyl 4-(methyl((3R,4R)-4-methyl-1-(pyrrolidine-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 13

isopropyl 4-(((3R,4R)-1-((S)-3-fluoropyrrolidine-1-carbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 14

ethyl 4-(((3R,4R)-1-((S)-3-fluoropyrrolidine-1-carbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 15

ethyl 4-(((3R,4R)-1-((R)-3-fluoropyrrolidine-1-carbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 16

isopropyl 4-(((3R,4R)-1-((R)-3-fluoropyrrolidine-1-carbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 17

2-methoxyethyl 4-(((3R,4R)-1-((R)-3-fluoropyrrolidine-1-carbonyl)-4-methylpiperidin-3-yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 18

2-methoxyethyl 4-(((3R,4R)-1-((S)-3-fluoropyrrolidine-1-carbonyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 19

2-methoxyethyl 4-(methyl((3R,4R)-4-methyl-1-(pyrrolidine-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 20

2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 21

2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 22

2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 23

2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperridin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 24

ethyl 4-(((3R,4R)-1-(2-caynoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b[pyridine-5-carboxylate 25

2-methoxyethyl 4-(((3S,4S)-4-methyl-1-propionylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate26

2-methoxyethyl 4-(((3S,4S)-1-butyryl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 27

2-methoxyethyl 4-(((3R,4R)-4-methyl-1-(3-methylbutanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 28

2-methoxyethyl 4-(((3S,4S)-4-methyl-1-propylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 29

2-methoxyethyl 4-(((3S,4S)-1-ethyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 30

methyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 31

ethyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 32

isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 33

methyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 34

ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 35

isopropyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 36

2-methoxyethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 37

2-hydroxyethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 38

methoxymethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 39

ethoxymethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 40

isopropoxymethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 41

isopropoxymethyl (S)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 42

isopropoxymethyl (R)-4-((1-acryloylpyrrolidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 43

isopropoxymethyl (S)-4-((1-acryloylpyrrolidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 44

isopropoxymethyl 4-((1-acryloylazetidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 45

methoxymethyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 46

ethyl 2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate 47

ethyl 3-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)propanoate 48

ethyl 4-((1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 49

ethyl 4-((1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 50

methyl 4-((1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 51

methyl 4-((1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 52

isopropyl 4-((1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 53

isopropyl 4-((1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 54

ethyl 4-((1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 55

ethyl 4-((1-(2-cyanoethyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 56

2-methoxyethyl 4-((1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 57

2-methoxyethyl 4-((1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 58

ethyl 4-((1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 59

ethyl 4-((1-acryloyl-6-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 60

ethyl 4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 61

methyl 4-((1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 62

methyl 4-((1-acryloyl-6-methylpiperidin-3-yl(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 63

isopropyl 4-((1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 64

isopropyl 4-((1-acryloyl-6-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 65

2-methoxyethyl 4-((1-acryloyl-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 66

2-methoxyethyl 4-((1-acryloyl-6-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 117

ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 118

methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 119

tert-butyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 123

ethyl (R)-4-((1-(2-cyanoethyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 124

isopropyl 4-(((3R,4R)-1-(2-(cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 125

propyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 126

ethyl 4-(((3R,4R)-1-(1-cyanocyclopropane-1-carbonyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 127

ethyl 4-(((3R,4R)-1-(2-cyanopropanoyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 128

ethyl (R)-4-((1-(1-cyanocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate129

ethyl 4-(((3R)-1-(2-cyanopropanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 130

propyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 131

2-methoxyethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 143

ethyl (S)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 144

ethyl (R)-4-((1-(2-cyano-2- methylpropanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 146

ethyl 4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 156

ethyl 4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate157

ethyl-4-(((R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate158

propyl 4-(((R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate159

isopropyl 4-(((R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate160

methyl 4-(((R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate170

methyl 4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 171

isopropyl 4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 172

propyl 4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 173

ethyl 4-(((3R,6S)-1-(2-cyano-2-methylpropanoyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 174

ethyl 4-(((3R,6S)-1-(2-cyanoethyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 175

cyclopropyl 4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 176

ethyl 4-(((3R,6S)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 177

ethyl 4-(((3R,6S)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 178

methyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 179

isopropyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 180

cyclopropyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 181

cyclopropyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 182

ethyl 4-(((3R,4R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 183

ethyl 4-(((3R,4R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 197

propyl 4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate198

ispropyl 4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate199

methyl 4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate

The invention is further illustrated by the following examples ofcompounds of Formula (II)

Example # Structure Name  67

methyl 4-((4-(2-cyanoacetoxy)-2-methylcyclohexyl)(methyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 68

ethyl 4-(((1R,3R)-3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  69

ethyl 4-(((1R,3R)-3-(2- cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  70

ethyl 4-(((1S,3S)-3-(2- cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  71

ethyl 4-(((1S,3S)-3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  72

ethyl 4-(((1R,3R)-3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  73

ethyl 4-(((1R,3R)-3-(2- cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  74

ethyl 4-(((1S,3S)-3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  75

ethyl 4-(((1S,3S)-3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  76

ethyl 4-(((1S,4S)-4-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  77

ethyl 4-(((1R,4R)-4-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  78

ethyl 4-(((1S,4S)-4-hydroxycyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  79

ethyl 4-(((1R,4R)-4-hydroxycyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  80

ethyl 4-(((1S,3R)-3-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  81

ethyl 4-(((1S,3S)-3-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  82

ethyl 4-(((1S,3S)-3-hydroxycyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  83

ethyl 4-(((1S,3R)-3-hydroxycyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  84

ethyl 4-(((1R,2R,5R)-5-hydroxy-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carbonyl  85

ethyl 4-(((1R,2R,54R)-5-hydroxy-2-methylcyclohexyl)(methyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 86

methyl 4-(((1R,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  87

isopropyl 4-(((1R,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  88

methyl 4-(((1R,3S,5s,7s)-5-hydroxyadamantan-2-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate  89

ethyl 4-(((1R,3S,5S,7S)-5-hydroxyadamantan-2-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate  90

isopropyl 4-(((1R,3S,5S,7S)-5-hydroxyadamantan-2-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate  91

2-fluoroethyl 4-(methyl)(1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  92

ethyl 4-(((1R,4R)-4-((N- methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  93

methyl 4-(methyl)((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  94

ethyl 4-(methyl((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  95

ethyl 4-(((1R,4R)-4-((N-ethylsulfamoyl)methyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  96

methyl 4-(((1R,4R)-4-((N-ethylsulfamoyl)methyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  97

2-Fluoroethyl 4-(((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  98

methyl 4-(((1R,4R)-4-((N- methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate  99

ethyl 4-(((1R,4R)-4-((N- ethylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 100

methyl 4-(((1R,4R)-4-((N- ethylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 101

ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 102

isopropyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 103

propyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 104

2-methoxyethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 105

ethyl 4-((4-hydroxy-2-methylcyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 106

isopropyl 4-((4-hydroxy-2-methylcyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 107

propyl 4-((4-hydroxy-2-methylcyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 108

2-methoxyethyl 4-((4-hydroxy-2-methylcyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 109

ethyl 4-((4-hydroxy-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 110

isopropyl 4-((4-hydroxy-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 111

propyl 4-((4-hydroxy-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 112

2-methoxyethyl 4-((4-hydroxy-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate 113

ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 114

isopropyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 115

propyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 116

2-methoxyethyl 4-((3-(2- cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 141

ethyl 4-((3-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 142

ethyl 4-((3-(cyanomethyl)-4-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 162

isopropyl 4-(methyl((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 163

propyl 4-(methyl((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 164

propyl 4-(((1R,4R)-4-((N- methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 165

isopropyl 4-(((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 166

methyl 4-(methyl((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 167

methyl 4-(((1R,4R)-4-((N- methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 184

propyl 4-(((1R,2s,3S,5r,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-carboxylate 185

cyclopropyl 4-(((1R,2s,3S,5r,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 195

methyl 4-(((1R,2s,3S,5r,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 196

isopropyl 4-(((1R,2s,3S,5r,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

The invention is further illustrated by the following examples ofcompounds of Formula (III)

Example # Structure Name 120

4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 121

(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 145

cyclopropylmethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl0amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 161

cyclopropylmethyl 4-((1-(2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate186

cyclopropylmethyl 4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine- 5-carboxylate 187

cyclopropylmethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine- 5-carboxylate

The invention is further illustrated by the following examples ofcompounds of Formula (IV)

Example # Structure Name 132

ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 133

(rac)-(cis)-Ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 134

(rac)-(trans)-Ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate135

(cis) Ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, enantiomer 1 136

(cis) Ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, enantiomer 2 137

(trans) Ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate enantiomer 1 138

(trans)-Ethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, enantiomer 2 139

(rac) (cis) Propyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate140

(rac)-(trans)-Propyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate147

4-(((1S,3R)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 148

racemic, trans -2-methoxyethyl 4-((3-(2-cyanoethy)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate 149

cis-2-methoxyethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate,enantiomer 1 150

cis 2-methoxyethyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate,enantiomer 2 151

trans-racemic-Methyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate152

cis-racemic-Methyl 4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate153

ethyl 4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 168

cyclopropylmethyl 4-(((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 169

cyclopropylmethyl 4-(methyl((1R,4R)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 188

isopropyl 4-(((1S,3S)-3-(2- cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 189

isopropyl 4-(((1R,3R)-3-(2- cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 190

cyclopropyl 4-(((1S,3S)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate191

cyclopropyl 4-(((1R,3R)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate192

cyclopropylmethyl 4-(((1S,3S)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate193

cyclopropylmethyl 4-(((1R,3R)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate194

cyclopropylmethyl 4-(((1R,2s,3S,5r,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3- b]pyridine-5-carboxylatePharmaceutical Compositions

Some embodiments herein are directed to a pharmaceutical compositioncomprising a compound of embodiments herein and a pharmaceuticallyacceptable carrier or diluent.

Also provided is a pharmaceutical composition comprising a compound asdisclosed herein, together with a pharmaceutically acceptable carrier.

While it may be possible for the compounds described herein to beadministered as the raw chemical, it is also possible to present them asa pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or a derivative thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. The pharmaceutical compositionsdisclosed herein may be manufactured in any manner known in the art,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

In some embodiments, the pharmaceutical compositions for use inaccordance with embodiments herein can be formulated in conventionalmanner using one or more physiologically acceptable carriers orexcipients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, intrathecal, intradural,transmucosal, transdermal, rectal, intranasal, topical (including, forexample, dermal, buccal, sublingual and intraocular), intravitreal, orintravaginal administration although the most suitable route may dependupon for example the condition and disorder of the recipient. Theformulation could include those suitable for administration by depotinjections or by implants. The formulation could include those suitablefor administration by inhalation, such as, for example, a gas, vapor, orpowder. The formulation could include those suitable for administration,e.g., as an aerosol via a nebulizer, humidifier, inhaler and vaporizeror the like. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Typically, these methods include the step of bringinginto association a compound disclosed herein or a derivative thereof(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose. In contrast, systemic administration refers to oral, intravenous,intraperitoneal and intramuscular administration.

In some embodiments, the compounds disclosed herein may be administeredophthalmically. In some embodiments, the compounds disclosed herein maybe administered as an ophthalmic composition. The compounds ofembodiments herein may be administered as, for example, liquidpreparations, including eye lotions, spray, or eye drops for topicaladministration. In some embodiments, the compounds disclosed herein maybe administered as semi-solid preparations, for example, applied to theeyelid, such as cream, lotion, gel, ointment, or paste. In someembodiments, the compounds disclosed herein may be administered as soliddosage forms, for example, applied to the eye surface to producemodified release, such as a powder. In some embodiments, the compoundsof embodiments herein are administered through devices for surgicalimplantation, parenteral products, (e.g., intracorneal or intravitreousproducts), liquids for irrigation, or the like. In some embodiments, thecomposition comprising the compounds disclosed herein are sterile andfree from particulate matters. In some embodiments, the compoundsdisclosed herein may be administered by intraocular injection,intraorbital injection, or an intravitreal injection. In someembodiments, the intraocular injection may be to the anterior chamber ofthe eye, posterior chamber of the eye, or a combination thereof. Forexample, the compounds disclosed herein may be administered to theposterior intraorbital region of the eye.

In some embodiments, formulations suitable for topical administrationinclude liquid or semi-liquid preparations suitable for penetrationthrough the skin to the site of inflammation such as a solution, powder,fluid emulsion, fluid suspension, semi-solid, ointment, paste, cream,gel, jelly, foam, liniment, lotion, and drops suitable foradministration to the eye, ear or nose. The active ingredient fortopical administration may comprise, for example, from 0.001% to 10% w/w(by weight) of the formulation. In certain embodiments, the activeingredient may comprise as much as 10% w/w. In other embodiments, it maycomprise less than 5% w/w. In certain embodiments, the active ingredientmay comprise from 2% w/w to 5% w/w. In other embodiments, it maycomprise from 0.1% to 1% w/w of the formulation.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C₁-C₆) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, and cosmeticagents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as steric or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by fungicidal agentssuitable for inclusion in the drops are phenylmercuric nitrate oracetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidineacetate (0.01%). Suitable solvents for the preparation of an oilysolution include glycerol, diluted alcohol and propylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered at a dose of from 0.1 to 500 mg/kg perday. The dose range for adult humans is generally from 5 mg to 2 g/day.Tablets or other forms of presentation provided in discrete units mayconveniently contain an amount of one or more compounds which iseffective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

When employed as pharmaceuticals, the compounds can be administered inthe form of pharmaceutical compositions. These compositions can beprepared in a manner well known in the pharmaceutical arts, and can beadministered by a variety of routes, depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration of the disclosed compounds or compositions may be oral,parenteral (including subcutaneous, intradermal, intramuscular,intravenous, intraarticular, and intramedullary), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), intraperitoneal, transmucosal,transdermal, rectal, topical (including dermal, buccal, sublingual andintraocular), or intravaginal administration. Parenteral administrationincludes intravenous, intraarterial, subcutaneous, intraperitoneal,intramuscular or injection or infusion; or intracranial, e.g.,intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions fortopical administration may include foams, transdermal patches,ointments, lotions, creams, gels, solutions, fluid emulsions, fluidsuspensions, semi-solids, pastes, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.Coated condoms, gloves and the like may also be useful. In someembodiments, the compounds can be contained in such formulations withpharmaceutically acceptable diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,preservatives and the like. The artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009); andGoodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13thEdition, McGraw Hill, New York (2018) can be consulted.

In some embodiments, a method of treating a JAK1 and/or JAK3 mediateddisease administering a pharmaceutical composition of embodimentsdisclosed herein. In some embodiments, the compound is in atherapeutically effective amount. In some embodiments, thetherapeutically effective amount is an amount disclosed herein.

Some embodiments disclosed herein also include pharmaceuticalcompositions which contain, as the active ingredient, one or more of thecompounds disclosed herein in combination with one or morepharmaceutically acceptable carriers (excipients).

In some embodiments, a method of making a pharmaceutical compositioncomprises mixing the active ingredient with an excipient, diluting theactive ingredient using an excipient, or enclosing the active ingredientwithin a carrier in the form of, for example, a capsule, sachet, paper,or other container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose,including eutectic solvents, eutectic-based ionic liquids, or ionicliquids. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions can be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound can be effective over a wide dosage range and can begenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

In some embodiments, the pharmaceutical composition may comprise about0.01% to about 50% of one or more compounds disclosed herein. In someembodiments, the one or more compounds is in an amount of about 0.01% toabout 50%, about 0.01% to about 45%, about 0.01% to about 40%, about0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%,about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about45%, about 0.05% to about 40%, about 0.05% to about 30%, about 0.05% toabout 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1%to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about0.1% to about 20%, about 0.1% to about 100%, about 0.1% to about 5%,about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about40%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% toabout 100%, about 0.5% to about 5%, about 1% to about 50%, about 1% toabout 45%, about 1% to about 40%, about 1% to about 35%, about 1% toabout 30%, about 1% to about 25%, about 1% to about 20%0, about 1% toabout 15%, about 1% to about 10%, about 1% to about 5%, about 5% toabout 45%, about 5% to about 40%, about 5% to about 35%, about 5% toabout 30%, about 5% to about 25%, about 5% to about 20%, about 5% toabout 15%, about 5% to about 10%, about 10% to about 45%, about 10% toabout 40%, about 10% to about 35%, about 10% to about 30%, about 10% toabout 25%, about 10% to about 20%, about 10% to about 15%, or a valuewithin one of these ranges. Specific examples may include about 0.01%,about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%,about 90%, or a range between any two of these values. The foregoing allrepresenting weight percentages of the composition. In some embodiments,the composition is suitable for topical administration. In someembodiments, the composition is suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, intrathecal, intradural,transmucosal, transdermal, rectal, intranasal, topical (including, forexample, dermal, buccal sublingual and intraocular), intravitreal orintravaginal administration.

In some embodiments, the compound is in a therapeutically effectiveamount. In some embodiments, the therapeutically effective amount may beabout 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg toabout 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg,about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg toabout 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg,about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mgto about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg,about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mgto about 500 mg, about 10 mg to about 300 mg, about 50 mg to about 300mg, from about 100 mg to about 300 mg, about 10 mg to about 150 mg,about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg toabout 120 mg or a range between any two of these values. Specificexamples include, for example, about 1000 mg, about 900 mg, about 800mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175mg, about 150 mg, about 125 mg, about 120 mg, about 110 mg, about 100mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg,about 30 mg, about 20 mg, or any value between the ranges disclosedabove.

In some embodiments, the therapeutically effective amount can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds can be provided in anaqueous physiological buffer solution containing about 0.1 to about 10%w/v of the compound for parenteral administration. Some typical doseranges for the compounds are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.

For preparing solid compositions such as tablets, the principal activeingredient can be mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally therapeuticallyeffective unit dosage forms such as tablets, pills and capsules. Thissolid pre-formulation is then subdivided into unit dosage forms of thetype described above containing from, for example, about 0.1 to about1000 mg of the active ingredient.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

In some embodiments, the compositions administered to a patient can bein the form of pharmaceutical compositions described above. In someembodiments, these compositions can be sterilized by conventionalsterilization techniques, or may be sterile filtered. Aqueous solutionscan be packaged for use as is, or lyophilized, the lyophilizedpreparation being combined with a sterile aqueous carrier prior toadministration. In some embodiments, the pH of the compound preparationsis about 3 to about 11, about 5 to about 9, about 5.5 to about 6.5, orabout 5.5 to about 7.5. It will be understood that use of certain of theforegoing excipients, carriers, or stabilizers will result in theformation of pharmaceutical salts.

Methods of Use

The present invention relates to a method of modulation of a JAK1 and/orJAK3-mediated function in a subject comprising the administration of atherapeutically effective amount of a compound as disclosed herein.

The present invention also relates to a method of inhibiting at leastone JAK1 and/or JAK3 function comprising the step of contacting JAK1and/or JAK3 with a compound as described herein. The cell phenotype,cell proliferation, activity of JAK1 and/or JAK3, change in biochemicaloutput produced by active JAK1 and/or JAK3, expression of JAK1 and/orJAK3, or binding of JAK1 and/or JAK3 with a natural binding partner maybe monitored. Such methods may be modes of treatment of disease,biological assays, cellular assays, biochemical assays, or the like.

Also provided herein is a method of treating a JAK1 and/or JAK3-mediateddisease comprising administering to a patient in need thereof atherapeutically effective amount of a compound as disclosed herein, aderivative thereof, or a combination thereof. In certain embodiments,the therapeutically effective amount of a compound as disclosed herein,a derivative thereof, or a combination thereof, may be in the form of apharmaceutical composition. In embodiments, the pharmaceuticalcomposition may include a pharmaceutically acceptable excipient.

In embodiments, diseases or disorders associated with a JAK1 kinaseand/or a JAK3 kinase that are treated by compounds of the presentinvention include autoimmune disorders, chronic inflammatory disorders,acute inflammatory disorders, auto-inflammatory disorders, fibroticdisorders, metabolic disorders, neoplasias, or cardiovascular orcerebrovascular disorders. Thus, in some embodiments, the presentinvention provides a method for treating a JAK1 and/or JAK3 mediateddisease or disorder in a patient in need thereof, wherein said methodcomprises administering to said patient a therapeutically effectiveamount of a provided compound, or composition thereof. Such JAK1 and/orJAK3-mediated diseases or disorders include, but are not limited to,those described herein.

In some embodiments, said JAK1 and/or JAK3-mediated disease or disorderis chosen from a skin disorder, pruritus, a hair loss disorder, acancer, a neoplasm, Alzheimer's disease, an inflammatory condition,connective tissue diseases and an autoimmune condition.

In certain embodiments, said JAK1 and/or JAK3-mediated disease ordisorder is a neoplasm, a malignancy, a myeloproliferative disorder, ahematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm,including myelofibrosis, primary myelofibrosis, polycythemia vera,essential thrombocythemia, acute and chronic leukemias, lymphomas,cutaneous lymphomas including mycosis fungoides, other myeloidmalignancies, and myelodysplastic syndrome.

In certain embodiments, said JAK1 and/or JAK3-mediated disease isselected from the group consisting of an autoimmune disorders orresponses, broad activation of the immune responses, bacterialinfection, viral infection, inflammation, a chronic and/or acuteinflammatory disorder or condition, and/or auto-inflammatory disorder,fibrotic disorders, metabolic disorders, a neoplasm, or cardiovascularor cerebrovascular disorders, a skin disorder, pruritus, a hair lossdisorder, a cancer or malignancy, autoimmune connective tissue diseasesand an autoimmune condition; Still's disease, adult-onset Still'sdisease, Th17-associated inflammation, polychondritis (e.g. relapsingpolychondritis); myositis, polymyositis, autoimmune myositis,dermatomyositis, juvenile dermatomyositis; myasthenia gravis; Arthritis(e.g. rheumatoid arthritis, juvenile rheumatoid arthritis,systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infectiousarthritis, inflammatory arthritis, inflammatory bowel disease-associatedarthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemicjuvenile idiopathic arthritis, psoriatic arthritis),spondylitis/spondyloarthritis/spondyloarthropathy (ankylosingspondylitis), gout, scleroderma (systemic scleroderma, juvenilescleroderma), Reiter's syndrome/reactive arthritis, lyme disease,lupus/systemic lupus erythematosus (SLE) (lupus erythematosus, pediatricsystemic lupus erythematosus, cutaneous lupus (subacute cutaneous lupus,chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus),polymyalgia rheumatica, enthesitis, mixed connective tissue disease,enthesopathy; carditis, myocarditis, angiogenesis disorders,myelodysplastic syndrome, atherosclerosis, restenosis (restenosis of anatherosclerotic coronary artery), acute coronary syndrome, myocardialinfarction, cardiac-allograft vasculopathy, transplant arteriopathy;vasculitis (large vessel vasculitis, small vessel vasculitis, giant-cellarteritis, polyarteritis nodosa, vasculitis syndromes including:Takayasu's arteritis, Wegener's granulomatosis, Behcet's Disease),stimulator of interferon genes (STING) associated vasculopathy withonset in infancy (SAVI); gastrointestinal disorders, enterocolitis,colitis, inflammatory bowel disease (ulcerative colitis, Crohn'sdisease), irritable bowel syndrome, enteritis syndrome/spastic colon,celiac disease; acute and chronic pancreatitis; primary biliarycirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (forexample, primary biliary cirrhosis or cirrhosis due to fatty liverdisease (for example, alcoholic and nonalcoholic steatosis);esophagitis, gastritis, gastric and duodenal ulcers, peritonitis;Nephropathies: immunologically mediated glomerulonephropathy, autoimmunenephropathy, membranous glomerulopathy, chronic progressivenephropathies, diabetic kidney disease/diabetic nephropathy, renalfibrosis, renal ischemic/reperfusion injury, HIV associated nephropathy,ureteral obstructive nephropathy, glomerulosclerosis, proteinuria,nephrotic syndrome, polycystic kidney disease, autosomal dominantpolycystic kidney disease, a nephropathy is an immunologically mediatednephropathy, autoimmune nephropathy, chronic progressive nephropathies,diabetic nephropathy, renal fibrosis, ischemic/reperfusion injuryassociated, HIV associated nephropathy, ureteral obstructivenephropathy, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension induced nephropathy,glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidneydisease, autosomal dominant polycystic kidney disease, diabetic kidneydisease, lupus nephritis; interstitial cystitis; periodontitis,gingivitis; pulmonary inflammation, sinusitis, pneumonia, bronchitis,asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis,bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD),interstitial lung disease (pulmonary fibrosis, idiopathic pulmonaryfibrosis), acute lung injury, pulmonary fibrosis (for example,idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructivepulmonary disease, adult respiratory distress syndrome, acute lunginjury, drug-induced lung injury; Meniere's disease; ocular disordersincluding, (e.g.), ocular inflammation, uveitis, dryeye/keratoconjunctivitis sicca, scleritis, episcleritis,keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis,retinopathy (diabetic retinopathy, immune mediated retinopathy, maculardegeneration, wet macular degeneration, dry (age related) maculardegeneration); Mastocytosis, iron deficiency anemia, uremia,hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD),myelodysplastic syndrome, idiopathic thrombocytic pupura; boneresorption diseases; Neurodegenerative disorders,neurological/neuromuscular disorders (e.g.), multiple sclerosis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myastheniagravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barretsyndrome, meningitis, encephalitis, traumatic brain injury; nervoussystem damage, delusional parasitosis, dysregulation of neuronalprocesses and sensory perception, stroke/neuronal ischemia, spinal cordinjury, peripheral neuropathy, tactile hallucinations, spinal cordinjury, psychiatric disease; pain (acute pain, chronic pain, neuropathicpain, or fibromyalgia) paresthetica, nerve irritation, peripheralneuropathy; pruritus/itch (atopic pruritus, xerotic pruritus, pruritusassociated with psoriasis/psoriatic itch/psoriasis-associated itch),acute pruritus, chronic pruritus, idiopathic pruritus, chronicidiopathic itch, biliary itch, hepatobiliary-associated itch, renalassociated itch/renal itch, uremic itch, cholestasis, intrahepaticcholestasis of pregnancy, lichen simplex chronicus associated pruritus,lymphoma-associated itch, leukemia-associated itch, prurigo nodularis,atopic dermatitis-associated itch, atopic itch/atopic puritis, bullousitch, brachioradial pruritus) neurogenic itch, neuropathic itch,notalgia paresthetica, pruritic popular eruption of HIV, psychogenicitch, swimmer's itch, pruritus or uremic itch, urticarial itch;dermatologic disorders (e.g.), dermatologic drug reactions/drugeruptions, xerosis/dryskin, skin rash, skin sensitization, skinirritation, sunburn, shaving, body louse, head lice/pediculosis, pubiclice, cutaneous larva migrans, scabies, parasitic infection, insectinfestation, urticarial/hives, popular uritcariaurticaria, insect bites,insect stings, dandruff, foreign objects or devices on skin, fungalinfection, herpes, varicella/chicken pox, eosinophilic folliculitis,dermatosis of pregnancy/pruritic urticarial papules and plaques ofpregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses,histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis,psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne(acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne,scarring acne, acne keloidalis nuchae), atopies (allergic contactsensitization, allergic dermatitis) dermatitis (atopicdermatitis/eczema, contact dermatitis, photodermatitis, seborrheicdermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis(Sweet's syndrome), chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperature syndrome (CANDLE Syndrome),hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia (eyebrowalopecia, intranasal hair alopecia, scarring alopecia (centralcentrifugal cicatricial alopecia), nonscarring alopecia (alopecia areata(AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU),ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata)),androgenetic/androgenic alopecia (AGA)/male and female pattern AGA),telogen effluvium, tinea capitis, hypotrichosis (hereditaryhypotrichosis simplex), lichen planopilaris (frontal fibrosingalopecia), punctate palmoplantar keratoderma, erythema elevatinumdiutinum (EED), neutrophilic eccrine hidradenitis, palisadingneutrophilic granulomatous dermatitis, neutrophilic urticarialdermatosis, vitiligo including segmental vitiligo (unisegmentalvitiligo, bisegmental vitiligo, multisegmental vitiligo) non-segmentalvitiligo (acral, facial, or acrofacial vitiligo, centrofacial vitiligo,mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginalinflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebnerphenomenon, vulgaris vitiligo, generalized vitiligo, universalvitiligo), mixed vitiligo/nonsegmental associated with segmentalvitiligo, focal vitiligo, solitary mucosal vitiligo or vitiligo with orwithout leukotricia (involvement of body hair); bullous diseases,immunobullous diseases (bullous pemphigoid, cicatricial pemphigoid,pemphigus vulgaris, linear IgA disease), gestational pemphigoid,xeroderma pigmentosum; disorders of fibrosis and scarring: fibroids,hepatic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, lowgrade scarring such as, scleroderma, increased fibrosis, keloids,post-surgical scars; wound healing, surgical scarring, radiation inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),CNS scarring, alimentary track or gastrointestinal fibrosis, renalfibrosis, hepatic or biliary fibrosis, liver fibrosis (for example,nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma),cardiac fibrosis (for example, endomyocardial fibrosis or atrialfibrosis), ophthalmic scarring, fibrosclerosis, scar growth, wound orscab healing, keloid, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis,nephrogenic systemic fibrosis; Sjorgren's syndrome, sarcoidosis,familial Mediterranean fever, Cryopyrin associated periodic syndrome(Muckle-Wells syndrome, familial cold auto-inflammatorysyndrome/familial cold uticaria/TNF receptor associated periodicsyndrome, neonatal-onset multisystem inflammatory disease), hyperoxiainduced inflammations, reperfusion injury, post-surgical trauma, tissueinjury, elevated temperature syndrome; diabetes (Type I diabetes, TypeII diabetes)/diabetes mellitus, Hashimoto's thyroiditis, Graves'disease, Addison's disease, Castleman's disease, hypcrparathyroidism,menopause, obesity, steroid-resistance, glucose intolerance, metabolicsyndrome, thyroid illness, hypophysitis; systemic immune senescence;autoimmune atrophic gastritis, autoimmune atrophic gastritis ofpernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia,sympathetic ophthalmia; secondary hematologic manifestations ofautoimmune diseases (for example, anemias), autoimmune hemolyticsyndromes (autoimmune hemolytic anemia), autoimmune and inflammatoryhepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia,silicone implant associated autoimmune disease, drug-inducedautoimmunity, HIV-related autoimmune syndromes, metal-inducedautoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergyand allergic reactions including hypersensitivity reactions such as TypeI hypersensitivity reactions, (e.g. including anaphylaxis), Type IIhypersensitivity reactions (e.g. Goodpasture's Disease, autoimmunehemolytic anemia), Type III hypersensitivity reaction diseases (e.g. theArthus reaction, serum sickness), and Type IV hypersensitivity reactions(e.g. contact dermatitis, allograft rejection); acute and chronicinfection, sepsis syndromes (sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome); acute and chronicinfection, sepsis syndromes (sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome); a rejection: graft vs.host reaction/graft vs. host disease, allograft rejections (for example,acute allograft rejection or chronic allograft rejection), earlytransplantation rejection; Malignancy, cancer, lymphoma, leukemia,multiple myeloma, a solid tumor, teratoma, metastatic and bonedisorders, internal cancers, cancer of the: bone, mouth/pharynx,esophagus, larynx, stomach, intestine, colon, rectum, lung (for example,non-small cell lung cancer or small cell lung cancer), liver (hepatic),pancreas, nerve, brain (for example, glioma, glioblastoma multiforme,astrocytoma, neuroblastoma, and schwannomas), head and neck, throat,ovary, uterus, prostate, testis, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eye (ocular malignancies), and skin(melanoma, keratocanthoma); as well as fibrotic cancers, fibroma,fibroadenomas, fibrosarcomas, a myeloproliferative disorder, neoplasm(hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm(myelofibrosis, primary myelofibrosis, polycythemia vera, essentialthrombocythemia)), leukemias (acute lymphocytic leukemia, acute andchronic myelogenous leukemia, chronic lymphocytic leukemia, acutelymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), orpromyelocytic leukemia), multiple myeloma and other myeloid malignancies(myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis(PMF), idiopathic myelofibrosis (IMF)), lymphomas (Hodgkin's disease,cutaneous lymphomas (cutaneous T-cell lymphoma, mycosis fungoides),lymphomas (for example, B-cell lymphoma, T-cell lymphoma, mantle celllymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors,Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma,rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroidfollicular cancer; increased accumulation of exogenous opioids orsynthetic opioids, notalgia paraesthetica, obsessive-compulsivedisorders, nostalgia associated with obsessive-compulsive disorders, anda combination thereof.

In some embodiments, additional exemplary disorders include, but are notlimited to: complications from organ transplants (includingxenotransplantation) such as graft vs. host reaction (for example, graftvs. host disease), allograft rejections (for example, acute allograftrejection or chronic allograft rejection), early transplantation,diabetes, a myeloproliferative disorder, a rejection (for example, acuteallograft rejection); bone resorption diseases, asthma (e.g., bronchialasthma), atopy, autoimmune thyroid disorders, chronic atypicalneutrophilic dermatosis with lipodystrophy and elevated temperaturesyndrome (CANDLE Syndrome), SAVI (stimulator of interferon genes (STING)associated vasculopathy with onset in infancy), ulcerative colitis,inflammatory bowel disease, Crohn's disease, celiac disease, ulcerativecolitis, Behcet's disease, myasthenia gravis, nephropathies, andmyocarditis, secondary hematologic manifestations of autoimmune diseases(for example, anemias), autoimmune hemolytic syndromes, autoimmune andinflammatory hepatitis, autoimmune ovarian failure, autoimmune orchitis,autoimmune thrombocytopenia, silicone implant associated autoimmunedisease, drug-induced autoimmunity, HIV-related autoimmune syndromes;acute and chronic infection, sepsis syndromes (e.g.) sepsis, septicshock, endotoxic shock, exotoxin-induced toxic shock, gram negativesepsis, gram positive sepsis, fungal sepsis, toxic shock syndrome;hyperoxia induced inflammations, reperfusion injury, post-surgicaltrauma, tissue injury, pain (e.g.) acute pain, chronic pain, neuropathicpain, or fibromyalgia.

In an embodiment, said vitiligo is segmental vitiligo includingunisegmental, bisegmental or multisegmental vitiligo, non-segmentalvitiligo including acral, facial, or acrofacial vitiligo, centrofacialvitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo,marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo,Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universalvitiligo, mixed vitiligo (nonsegmental associated with segmentalvitiligo), focal vitiligo, solitary mucosal vitiligo or vitiligo with orwithout leukotricia (involvement of body hair) or any type of vitiligoset forth in Table 1 below:

TABLE 1 Classification of vitiligo. NOMENCLATURE SUBSET NOTESNon-segmental Acrofacial Usually limited to face, head, hands, and feetvitiligo Generalized Symmetrical macules, mainly hands, fingers, face,and trauma-exposed areas Mucosal (at least Involvement of the oraland/or genital mucosae two sites involved) with other sites of skininvolvement Universal Depigmentation affects 80%-90% of body surface.Segmental vitiligo Unisegmental One or more depigmented maculesdistributed on one side of the body Bisegmental Two segmental lesionsdistributed either unilaterally or bilaterally Plurisegmental Multiplesegmental lesions distributed either unilaterally or bi-laterally Mixedvitiligo Occurrence of SV SV followed by NSV with a delay of at least 6and NSV months. At least 20% of a dermatomal segment affected by SV.Unclassified vitiligo Focal vitiligo Isolated macules that do not have asegmental distribution. No evolution into NSV after at least 2 yearsMucosal vitiligo Exclusive involvement of the oral or genital (only onesite mucosae involved)

In an embodiment, said skin disorder is atopic dermatitis, psoriasis,psoriasis vulgaris, skin sensitization, skin irritation, skin rash,contact dermatitis, allergic contact sensitization, allergic dermatitis,inflammatory dermatoses, or neutrophilic dermatoses.

“Pruritus”, as used herein, is interchangeable with “itch.” In someembodiments, pruritus includes chronic idiopathic pruritus, as well aspruritic components of other pruritic disorders. In some embodiments,pruritus may be a symptom of a disease or condition selected from thegroup consisting of: allergic reaction, arthropod bites, athlete's foot,atopic dermatitis (AD), atopic itch, atopic dermatitis-associated itch,autoimmune responses, autoimmune connective tissue disease, bacterialinfection, biliary itch, broad activation of the immune responses, bodylouse, bullous diseases, brachioradial pruritus, brain tumors, chronicidiopathic pruritus, contact dermatitis, cholestasis, cutaneous larvamigrans, cutaneous T-cell lymphoma, nervous system damage, dandruff,delusional parasitosis, dermatomyositis, dermatosis of pregnancy,diabetes mellitus, drug eruptions, dysregulation of neuronal processesand sensory perception, eczema, eosinophilic folliculitis, foreignobjects or devices on skin, fungal infection, gestational pemphigoid,head lice, herpes, hidradenitis suppurativa, hives, Hodgkin's disease,hyperparathyroidism, idiopathic chronic itch, inflammation, insectinfestation, insect bites, insect stings, intrahepatic cholestasis ofpregnancy, iron deficiency anemia, increased accumulation of exogenousopioids or synthetic opioids, internal cancer, jaundice, lichen planus,lichen sclerosus, lupus erythematosus, lymphoma, lymphoma-associateditch, leukemia-associated itch, malignancy, mastocytosis, menopause,multiple sclerosis, neoplasm, nerve irritation, neurogenic itch,neuropathic itch, notalgia paresthetica, notalgia obsessive-compulsivedisorders, paresthetica, parasitic infection, popular urticaria,pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera,psychiatric disease, psychogenic itch, pruritic popular eruption of HIV,pruritic urticarial papules and plaques of pregnancy (PUPPP), psoriasis,psoriasis-associated itch, psoriatic itch, pubic lice, punctatepalmoplantar keratoderma, renal itch, rheumatoid arthritis, scabies,scar growth, shaving, seborrheic dermatitis, stasis dermatitis, sunburn,swimmer's itch, systemic immune senescence, tactile hallucinations,Th17-associated inflammation, thyroid illness, uremia, pruritus oruremic itch, urticaria, urticarial itch, varicella, viral infection,wound or scab healing, and xerosis.

In an embodiment, the hair loss disorder is selected from alopecia,alopecia areata, patchy alopecia areata, alopecia totalis, alopeciauniversalis, ophiasis pattern alopecia areata, sisaihpo pattern alopeciaareata, androgenetic alopecia (male and female pattern hair loss),telogen effluvium, tinea capitis, hypotrichosis, hereditaryhypotrichosis simplex, scarring alopecia, lichen planopilaris, centralcentrifugal cicatricial alopecia, or frontal fibrosing alopecia.

In an embodiment, the connective tissue disease is selected from SLE(systemic lupus erythematosus), cutaneous lupus (e.g. SCLE, discoidlupus), chilblain lupus erythematosus, myositis, polymyositis,dermatomyositis, scleroderma, Sjogren's syndrome, polychondritis(relapsing polychondritis), vasculitis, or large vessel vasculitis.

In an embodiment, the nephropathy is selected from an immunologicallymediated nephropathy, autoimmune nephropathy, chronic progressivenephropathies, diabetic nephropathy, renal fibrosis,ischemic/reperfusion injury associated, HIV associated nephropathy,ureteral obstructive nephropathy, glomerulosclerosis, proteinuria,nephrotic syndrome, polycystic kidney disease, autosomal dominantpolycystic kidney disease or diabetic kidney disease.

In an embodiment, said cancer is a solid tumor.

In an embodiment, said cancer is prostate cancer, renal cancer, hepaticcancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma,Castleman's disease or pancreatic cancer.

In an embodiment, said cancer is lymphoma, leukemia, or multiplemyeloma.

In an embodiment, said myeloproliferative disorder (MPD) is polycythemiavera (PV), essential thrombocythemia (ET), myeloid metaplasia withmyelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenousleukemia (CML), chronic myelomonocytic leukemia (CMML),hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), orsystemic mast cell disease (SMCD).

In an embodiment, said myeloproliferative disorder is myelofibrosis.

In an embodiment, said myeloproliferative disorder is primarymyelofibrosis (PMF).

In an embodiment, said bone resorption disease is osteoporosis,osteoarthritis, bone resorption associated with hormonal imbalance, boneresorption associated with hormonal therapy, bone resorption associatedwith autoimmune disease, or bone resorption associated with cancer.

In some embodiments, the JAK1 and/or JAK-3-mediated disease or disorderis a fibrotic disorder. Exemplary fibrotic disorders include systemicsclerosis/scleroderma, lupus nephritis, connective tissue disease, woundhealing, surgical scarring, spinal cord injury, CNS scarring, acute lunginjury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosisor cystic fibrosis), chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension induced nephropathy, alimentarytrack or gastrointestinal fibrosis, renal fibrosis, hepatic or biliaryfibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis,hepatitis C, or hepatocellular carcinoma), cirrhosis (for example,primary biliary cirrhosis or cirrhosis due to fatty liver disease (forexample, alcoholic and nonalcoholic steatosis), radiation inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),primary sclerosing cholangitis, restenosis, cardiac fibrosis (forexample, endomyocardial fibrosis or atrial fibrosis), ophthalmicscarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma,fibroadenomas, fibrosarcomas, transplant arteriopathy, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, and nephrogenic systemic fibrosis.

In some embodiments, the JAK1 and/or JAK-3-mediated disease or disorderis a metabolic disorder. Exemplary metabolic disorders include obesity,steroid-resistance, glucose intolerance, and metabolic syndrome. In someembodiments, the JAK1 and/or JAK-3-mediated disease or disorder is aneoplasia. Exemplary neoplasias include cancers. In some embodiments,exemplary neoplasias include angiogenesis disorders, multiple myeloma,leukemias (for example, acute lymphocytic leukemia, acute and chronicmyelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, or promyelocytic leukemia), lymphomas (for example, B-celllymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma,Burkitt's lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin'sdisease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma,teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma,thyroid follicular cancer, Kaposi's sarcoma, melanoma, teratoma,rhabdomyosarcoma, metastatic and bone disorders, as well as cancer ofthe bone, mouth/pharynx, esophagus, larynx, stomach, intestine, colon,rectum, lung (for example, non-small cell lung cancer or small cell lungcancer), liver, pancreas, nerve, brain (for example, glioma orglioblastoma multiforme), head and neck, throat, ovary, uterus,prostate, testis, bladder, kidney, breast, gall bladder, cervix,thyroid, prostate, and skin.

In some embodiments, the JAK1 and/or JAK-3-mediated disorder is acardiovascular or cerebrovascular disorder. Exemplary cardiovasculardisorders include atherosclerosis, restenosis of an atheroscleroticcoronary artery, acute coronary syndrome, myocardial infarction,cardiac-allograft vasculopathy and stroke. Exemplary cerebrovasculardiseases include central nervous system disorders with an inflammatoryor apoptotic component, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury,neuronal ischemia and peripheral neuropathy.

Also provided herein is a compound as disclosed herein for use as amedicament.

Also provided herein is a compound as disclosed herein for use as amedicament for the treatment of a JAK1 and/or JAK3-mediated disease.

Also provided is the use of a compound as disclosed herein as amedicament.

Also provided is the use of a compound as disclosed herein as amedicament for the treatment of a JAK1 and/or JAK3-mediated disease.

Also provided is a compound as disclosed herein for use in themanufacture of a medicament for the treatment of a JAK1 and/orJAK3-mediated disease.

Also provided is the use of a compound as disclosed herein for thetreatment of a JAK1 and/or JAK3-mediated disease.

Also provided herein is a method of inhibition of JAK1 and/or JAK3comprising administering a compound as disclosed herein, or a derivativethereof.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient, whereinthe effect is chosen from cognition enhancement.

In certain embodiments, the JAK1 and/or JAK3-mediated disease is chosenfrom pruritus, alopecia, alopecia areata, vitiligo, male patternandrogenetic alopecia, female pattern androgenetic alopecia, atopicdermatitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis.

The compounds can be administered in various modes, e.g. oral,parenteral (including subcutaneous, intradermal, intramuscular,intravenous, intraarticular, and intramedullary), intraperitoneal,intrathecal, intradural, transmucosal, transdermal, rectal, intranasal,topical (including, for example, dermal, buccal, sublingual andintraocular), intravitreal, or intravaginal administration. The specificdose level for any particular patient will depend upon a variety offactors including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination, theprecise disorder being treated, and the severity of the indication orcondition being treated. Also, the route of administration may varydepending on the condition and its severity.

Thus, in another aspect, certain embodiments provide methods fortreating JAK1 and/or JAK3-mediated disorders in a human or animalsubject in need of such treatment comprising administering to saidsubject an amount of a compound disclosed herein effective to reduce orprevent said disorder in the subject, in combination with at least oneadditional agent for the treatment of said disorder that is known in theart. In a related aspect, certain embodiments provide therapeuticcompositions comprising at least one compound disclosed herein incombination with one or more additional agents for the treatment of JAK1and/or JAK3-mediated disorders.

In certain embodiments, a topically or orally administered JAK1 and/orJAK3 inhibitor/antagonist described herein can be used for the treatmentof alopecia areata (e.g. patchy alopecia areata, alopecia totalis,alopecia universalis) alone or in combination with topical orintralesional corticosteroids, topical minoxidil, oral finasteride, oraldutasteride, contact sensitization therapy such as with squaric aciddibutyl ester, dinitrochlorobenzene, diphencyprone, topical or oralmethoxalen and ultraviolet a (PUVA), topical anthralin, hairtransplantation procedures, or other therapies known to have beneficialeffects in the condition.

In certain embodiments, a topically or orally administered JAK1 and/orJAK3 inhibitor/antagonist disclosed herein can be used for the treatmentof male or female-pattern baldness (androgenetic alopecia) alone or incombination with topical minoxidil, oral finasteride (in male), oraldutasteride (in male), topical antiandrogens, hair transplantationprocedures, or other therapies known to have beneficial effects in thecondition.

In certain embodiments, the compounds may be used for the treatment ofvitiligo (e.g. localized vitiligo, focal vitiligo, generalized vitiligo,segmental vitiligo, acral vitiligo, facial vitiligo, acrofacialvitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo,marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo,Koebner phenomenon, vulgaris vitiligo, mixed acrofacial and vulgarisvitiligo, or universal vitiligo) alone or in combination with topicalcorticosteroids, topical tacrolimus, topical pimecrolimus, phototherapysuch as ultraviolet light therapy with UVB, narrow-band UVB, oral ortopical psoralen plus ultraviolet A (PUVA), calcipotriene or othertopical vitamin D analogs, excimer laser phototherapy, systemicimmunosuppressive agents, surgical treatments such as skin minigrafting,transplantation of autologous epidermal suspension, camouflage such aswith make-up or dihydroxyacetone and such, or other therapies known tohave beneficial effects in the condition.

Specific JAK1 and/or JAK3-mediated diseases to be treated by thecompounds, compositions, and methods disclosed herein include a skindisorder, pruritus, cancer, Alzheimer's disease, an inflammatorycondition, and an autoimmune condition.

In an embodiment, said skin disorder is pruritus, atopic dermatitis,psoriasis, acne vulgaris, comedonal acne, inflammatory acne,nodulo-cystic acne, scarring acne, hidradenitis suppurativa, pyodermagangrenosum, skin sensitization, skin irritation, skin rash, contactdermatitis or allergic contact sensitization.

In an embodiment, said bone resorption disease is osteoporosis,osteoarthritis, bone resorption associated with hormonal imbalance, boneresorption associated with hormonal therapy, bone resorption associatedwith autoimmune disease, or bone resorption associated with cancer.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Combination Therapy

The compounds and pharmaceutical compositions of the present disclosuremay be used to prevent or treat a JAK-mediated disorder by thesequential or co-administration of another pharmaceutical agent.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein, or a derivative thereof, incombination with another pharmaceutical agent. By way of example only,if one of the side effects experienced by a patient upon receiving oneof the compounds herein is hypertension, then it may be appropriate toadminister an anti-hypertensive agent in combination with the initialpharmaceutical agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may onlyhave minimal therapeutic benefit, but in combination with anotherpharmaceutical agent, the overall therapeutic benefit to the patient isenhanced). Or, by way of example only, the benefit of experienced by apatient may be increased by administering one of the compounds describedherein with another pharmaceutical agent (which also includes atherapeutic regimen) that also has therapeutic benefit. By way ofexample only, in a treatment for diabetes involving administration ofone of the compounds described herein, increased therapeutic benefit mayresult by also providing the patient with another pharmaceutical agentfor diabetes. In any case, regardless of the disease, disorder orcondition being treated, the overall benefit experienced by the patientmay simply be additive of the two pharmaceutical agents or the patientmay experience a synergistic benefit.

Specific, non-limiting examples of possible combination therapiesinclude use of compounds of embodiments herein with: chemotherapeutic oranti-proliferative agent, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating cardiovascular disease, an agent for treatingdiabetes, or an agent for treating immunodeficiency disorders.

Specific, non-limiting examples of possible combination therapies forinflammation include use of certain compounds of the disclosure with:(1) corticosteroids, including but not limited to cortisone,dexamethasone, and methylprednisolone; (2) nonsteroidalanti-inflammatory drugs (NSAIDs), including but not limited toibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON™),flurbiprofen (ANSAID™), ketoprofen, oxaprozin (DAYPRO™), diclofenacsodium (VOLTAREN™), diclofenac potassium (CATAFLAM™), etodolac(LODINE™), indomethacin (INDOCIN™), ketorolac (TORADOL™), sulindac(CLINORIL™), tolmetin (TOLECTIN™), meclofenamate (MECLOMEN™), mefenamicacid (PONSTEL™), nabumetone (RELAFEN™) and piroxicam (FELDENE™); (3)immunosuppressants, including but not limited to methotrexate(RHEUMATREX™), leflunomide (ARAVA™), azathioprine (IMURAN™),cyclosporine (NEORAL™, SANDIMMUNE™), tacrolimus and cyclophosphamide(CYTOXAN™); (4) CD20 blockers, including but not limited to rituximab(RITUXAN™); (5) Tumor Necrosis Factor (TNF) blockers, including but notlimited to etanercept (ENBREL™), infliximab (REMICADE™) and adalimumab(HUMIRA™); (6) interleukin-1 receptor antagonists, including but notlimited to anakinra (KINERET™); (7) interleukin-6 inhibitors, includingbut not limited to tocilizumab (ACTEMRA™); (8) interleukin-17inhibitors, including but not limited to AIN457; (9) Janus kinaseinhibitors, including but not limited to tasocitinib; and (10) sykinhibitors, including but not limited to fostamatinib.

Specific, non-limiting examples of possible combination therapies forthe treatment of cancer include use of certain compounds of thedisclosure with: (1) alkylating agents, including but not limited tocisplatin (PLATIN™), carboplatin (PARAPLATIN™), oxaliplatin (ELOXATIN™),streptozocin (ZANOSAR™), busulfan (MYLERAN™) and cyclophosphamide(ENDOXAN™); (2) anti-metabolites, including but not limited tomercaptopurine (PURINETHOL™), thioguanine, pentostatin (NIPENT™),cytosine arabinoside (ARA-C™), gemcitabine (GEMZAR™), fluorouracil(CARAC™), leucovorin (FUSILEV™) and methotrexate (RHEUMATREX™); (3)plant alkaloids and terpenoids, including but not limited to vincristine(ONCOVIN™), vinblastine and paclitaxel (TAXOL™); (4) topoisomeraseinhibitors, including but not limited to irinotecan (CAMPTOSAR™),topotecan (HYCAMTIN™) and etoposide (EPOSIN™); (5) cytotoxicantibiotics, including but not limited to actinomycin D (COSMEGEN™),doxorubicin (ADRIAMYCIN™), bleomycin (BLENOXANE™) and mitomycin(MITOSOL™); (6) angiogenesis inhibitors, including but not limited tosunitinib (SUTENT™) and bevacizumab (AVASTIN™); (7) tyrosine kinaseinhibitors, including but not limited to imatinib (GLEEVEC™), erlotinib(TARCEVA™), lapatininb (TYKERB™) and axitinib (INLYTA™); and (8) immunecheckpoint inhibitors, including but not limited to atezolizumab(TECENTRIQ™), avelumab (BAVENCIO™), durvalumab (IMFINZI™), ipilimumab(YERVOY™), pembrolizumab (KEYTRUDA™), nivolumab (OPDIVO™), andtremelimumab.

In some embodiments, the compounds disclosed in embodiments herein canalso be co-administered (concurrently or sequentially) with a variety ofother pharmaceutical agents or treatments, for example, pharmaceuticalagents or treatments that are administered systemically, such as orallyor parenterally. Examples of such systemic treatments include topical orsystemic corticosteroids (such as prednisone), antibiotics (such aserythromycin, tetracycline, and dicloxacillin), antifungal agents (suchas ketoconazole and fluconazole sold under the tradename Diflucan™),antiviral agents (such as valacyclovir sold under the tradenameValtrex™, acyclovir, and famciclovir sold under the tradename Famvir™),corticosteroids, immunosuppressants (such as cyclophosphamide sold underthe tradename Cytoxan™, azathioprine, methotrexate, mycophenolate),biologics (such as rituximab sold under the tradename Rituxan™,etanercept sold under the tradename Enbrel™, adalimumab sold under thetradename Humira™, infliximab sold under the tradename Remicade™,ustenkinumab sold under the tradename Stelara™, and alefacept sold underthe tradename Amevive™), and/or thyroid hormone replacement.

In some embodiments, other therapies that can be used in combinationwith the compounds disclosed herein include, for example,mercaptopurine, topical or systemic corticosteroids such as prednisone,methylprednisolone and prednisolone, alkylating agents such ascyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimusand tacrolimus, inhibitors of inosine monophosphate dehydrogenase(IMPDH) such as mycophenolate, mycophenolate mofetil, azathioprine,various antibodies, for example, antilymphocyte globulin (ALG),antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3),and irradiation. These various agents can be used in accordance withtheir standard or common dosages, as specified in the prescribinginformation accompanying commercially available forms of the drugs (seealso, the prescribing information in the 2006 Edition of The Physician'sDesk Reference). In some embodiments, standard dosages of these agentsmay be reduced when used in combination with the compounds ofembodiments herein. Without limiting the scope of this disclosure, it isbelieved the such combination may result in synergistic results withbetter efficacy, less toxicity, longer duration of action, or quickerresponse to therapy. In some embodiments, the combination therapies inembodiments herein may be administered in sub-therapeutic amounts ofeither the compounds of embodiments herein or the additionalpharmaceutical agents, or both. Azathioprine is currently available fromSalix Pharmaceuticals, Inc. under the brand name Azasan™; mercaptopurineis currently available from Gate Pharmaceuticals, Inc. under the brandname Purinethol™; prednisone and prednisolone are currently availablefrom Roxane Laboratories, Inc.; methyl prednisolone is currentlyavailable from Pfizer; sirolimus (rapamycin) is currently available fromWyeth-Ayerst under the brand name Rapamune™; tacrolimus is currentlyavailable from Fujisawa under the brand name Prograf™; cyclosporine iscurrent available from Novartis under the brand name Sandimmune™ andAbbott under the brand name Gengraf™; IMPDH inhibitors such asmycophenolate mofetil and mycophenolic acid are currently available fromRoche under the brand name Cellcept™ and Novartis under the brand nameMyfortic™; azathioprine is currently available from Glaxo Smith Klineunder the brand name Imuran™; and antibodies are currently availablefrom Ortho Biotech under the brand name Orthoclone™, Novartis under thebrand name Simulect™ (basiliximab) and Roche under the brand nameZenapax™ (daclizumab).

In some embodiments, the compounds of embodiments herein areadministered in conjunction, concomitantly or adjunctively, with thepharmaceutical agents or therapies above and/or with a pharmaceuticalagent or therapy for another disease. For example, the compounds ofembodiments herein may be combined with thyroid hormone replacementtherapy or with anti-inflammatory or immunomodulatory therapies.

In some embodiments, the combination therapies in embodiments herein maybe administered in sub-therapeutic amounts of either the compounds ofembodiments herein or the additional pharmaceutical agents, or both.

In any case, the multiple pharmaceutical agents (at least one of whichis a compound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple pharmaceutical agentsmay be provided in a single, unified form, or in multiple forms (by wayof example only, either as a single pill or as two separate pills). Oneof the pharmaceutical agents may be given in multiple doses, or both maybe given as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes toeight weeks or at any interval appropriate to maintain the desiredtherapeutic efficacy. In some embodiments, the timing between themultiple doses may be a minute, an hour, six hours, a day, two days,three days, four days, five days, six days, a week, two weeks, threeweeks, four weeks, five weeks, six weeks, seven weeks or eight weeks.

One or more additional pharmaceutical agents such as, for example,anti-inflammatory agents, steroids, immunosuppressants, as well as oneor more other ITK kinase inhibitors and/or other kinase inhibitors, suchas JAK3 kinase, JAK1 kinase, JAK1/2 kinase, or JAK2 kinase inhibitors,such as, for example, those described in WO 99/65909, WO 00/00202,and/or WO/2004/099205, or other agents can be used in combination withthe compounds of the present invention for treatment of JAK1 and/orJAK3-associated diseases, disorders or conditions.

In certain embodiments, the additional pharmaceutical agent is selectedfrom taxanes, inhibitors of bcr-abl, inhibitors of EGFR, DNA damagingagents, antimetabolites, paclitaxel, imatinib, dasatinib, nilotinib,erlotinib, gefitinib, cisplatin, oxaliplatin, carboplatin,anthracyclines, AraC, 5-FU, camptothecin, doxorubicin, idarubicin,paclitaxel, docetaxel, vincristine, a MEK inhibitor, U0126, a KSPinhibitor, vorinostat, pembrolizumab, nivolumab, atezolizumab, avelumab,tremelimumab, and durvalumab.

In some embodiments, said composition further comprises an additionalpharmaceutical agent selected from a chemotherapeutic oranti-proliferative agent, antiviral, antibiotic, antihistamine, anemollient, systemic phototherapy, psoralen photochemotherapy, lasertherapy, hormone replacement therapy, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating cardiovascular disease, an agent for treatingdiabetes, and an agent for treating immunodeficiency disorders.

In some embodiments, one or more compounds of the embodiments herein canbe used in combination with one or more other therapeutics used in thetreatment of JAK-mediated disorders, and may improve the treatmentresponse as compared to the response to the other therapeutics alone,without exacerbation of its toxic effects. In some embodiments,compounds of embodiments herein can be used in combination with one ormore other ITK inhibitors, and/or JAK1 and/or JAK3 inhibitors and/orJAK2 inhibitors and/or TYK2 inhibitors for the treatment of JAK-mediateddisorders. Additive or synergistic effects are desirable outcomes ofsuch combinations. The additional agents can be combined with thepresent compounds in a single or continuous dosage form, or the agentscan be administered simultaneously or sequentially as separate dosageforms. In some embodiments, one or more additional agents can beadministered to a patient in combination with at least one JAK1 and/orJAK3 inhibitor/antagonist described herein where the additional agentsare administered intermittently as opposed to continuously.

General Synthetic Methods for Preparing Compounds

Compounds of the present invention can be prepared using methodsillustrated in general synthetic schemes and experimental proceduresdetailed below. General synthetic schemes and experimental proceduresare presented for purposes of illustration and are not intended to belimiting. Starting materials used to prepare compounds of the presentinvention are commercially available or can be prepared using routinemethods known in the art. Representative procedures for the preparationof compounds of the invention are outlined in Schemes 1-5 below.Additional schemes used for analogs are provided in the examples.Solvents and reagents, whose synthetic preparations are not describedbelow, can be purchased at Sigma-Aldrich or Fisher Scientific.Additional schemes for the synthesis of specific analogs are alsoprovided in the example section.

Scheme 1 depicts the general synthesis of compounds of Formula (I) whereR₁, R₂, R₃, and R₄ are defined as above, n is 0, 1 or 2, and X is ahalogen. PG₁ is an indole protecting group such as benzenesulfonyl,toluenesulfonyl, mesitylenesulfonyl, t-butylcarbamate (Boc), allyl,benzyl, triisopropylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM),or p-methoxybenzyl. PG₂ is a secondary amine protecting group such as1-butylcarbamate (Boc), benzyl carbamate (Cbz), benzyl (Bn),p-methoxybenzyl (PMB), or N-acetyl (Ac). Compound CI is formed bycoupling DI with EI. Removing the amine protecting group PG₂ yieldscompound BI. Coupling of BI with a compound of formula HOR₄ or halo-R₄yields compound AI. Finally, removal of indole protecting group PG₁yields a compound of Formula (I). Alternatively, one could remove bothprotecting groups of CI and couple the intermediate with a compound offormula HOR₄ to yield compound I.

Scheme 2 illustrates a general synthesis for compounds of Formula I incases when R₁ is a —CO₂R₅ group. Commercially available ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (CAS #885500-55-0) canbe protected using SEM-Cl under standard reaction conditions using abase such as sodium hydride in a solvent such as DMF or THF followed bythe addition of SEM-Cl. The synthesis of diamine 3 (CAS #1251908-18-5)has been described previously (Shirakami et al., WO 2010119875) and maybe converted to intermediate 3a by the reduction of the Boc protectinggroup with lithium aluminum hydride in a solvent such as THF.Alternatively, diamine 3 (CAS #1251908-18-5) may be deprotected usingTFA in methylene chloride to give 3b. The secondary or primary amines 3aor 3b may be used to replace the chloride of 2 via nucleophilic aromaticsubstitution by heating in a solvent such as NMP. The resulting benzylprotected amine 4a or 4b can be deprotected with palladium on carbon ina solvent such as methanol. Once deprotected, amine 5a or 5b may becoupled with a variety of carboxylic acids under standard amide couplingprocedures; reaction with acid 6 using tripropylphosphonic anhydridewith triethylamine in dichloromethane is shown by way of example. Finaldeprotection using tetra-butylammonium fluoride in THF can produce thefinal compound 8a, ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateor 8b, ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Other amines may be utilized in addition to 3a and 3b. For instance,(R)-1-benzylpiperidin-3-amine may be used and the corresponding analogslacking a methyl group on the piperidine may be synthesized.

Analogs that have linkers between the carbonyl group of the ester andthe pyrrolopyridine core may be accessed by methods described in Scheme3. Commercially available4-chloro-1-[tris(1-methylethyl)silyl]-1H-pyrrolo[2,3-b]pyridine (9) maybe selectively lithiated at the 5 position using s-BuLi (Heinrich etal., J. Med. Chem. 2013) and reacted with I₂ to produce4-chloro-5-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10).Alternatively, the lithiated intermediate may be reacted directly withan electrophile such as ethyl 2-bromoacetate to produce intermediate 12.Other electrophiles such as allyl bromide could be used with the esterformed in subsequent steps by known methods. Compound 10 may betransformed in a variety of ways by palladium catalyzed cross couplingto produce analogs of interest. Illustrated here is reaction with ethylacrylate (Heck reaction) followed by reduction of the double bond toproduce intermediate 11. Intermediates 11 and 12 may be transformed intoJAK inhibitors by the methods described in Scheme 2 using a protecteddiamine such as (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine or(3R,4R)-1-benzyl-4-methylpiperidin-3-amine.

Scheme 4 depicts the general synthesis of compounds of Formula (II).R₁₀, R₂₀, R₃₀, and R₄₀ are defined as above, n is 0 or 1, and X is ahalogen. PG₁₀ is an indole protecting group such as benzenesulfonyl,toluenesulfonyl, mesitylenesulfonyl, t-butylcarbamate (Boc), allyl,benzyl, triisopropylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM),or p-methoxybenzyl. Compound FII is formed by reductive amination of GIIwith a compound of formula NH₂R₂₀. Compound DII is formed by thecoupling of FII with a compound of formula EII. Compound CII is formedby removing the ketal group from a compound of DII. Compound BII isformed by the reduction of a ketone from a compound of Formula CII usingsodium borohydride. Compound AII is formed by the coupling of a compoundof Formula BII with a compound of formula HOR₄₀ under standard acylationor alkylation conditions. Finally, removal of indole protecting groupPG₁₀ yields a compound of Formula (II). In some cases BII is deprotectedto provide II where R₄₀ is OH.

Compounds of Formula II may be produced by the methods described inScheme 5 which illustrates the synthesis of methyl4-((4-(2-cyanoacetoxy)-2-methylcyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. Commerciallyavailable 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (13) can be convertedto N,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-amine (15) by reductiveamination using sodium cyanoborohydride. Nucleophilic aromaticsubstitution of an aromatic chloride such as 16 with 15 under thermalconditions in water or NMP provides ketal protected intermediate 17.Deprotection followed by reduction can produce alcohol 19. Esterformation and deprotection results in the final analog 22.

While the invention has been particularly shown and described withreference to preferred embodiments and various alternate embodiments, itwill be understood by persons skilled in the relevant art that variouschanges in form and details can be made without departing from thespirit and scope of the invention. All printed patents and publicationsreferred to in this application are hereby incorporated herein in theirentirety by this reference.

Exemplary synthetic methods for certain compounds detailed in theexample section are further illustrated by the following:

Synthesis of Example 1: Preparation of ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Preparation of (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine

To a solution of tert-butyl((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)carbamate (1 g, 3.28 mmol) intetrahydrofuran (20 mL), was added lithium aluminium hydride (4.9 mL,4.9 mmol, 1M in THF) and mixture was heated to 60° C. for 5 hours. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith water, brine and dried over anhydrous sodium sulfate. The solutionwas filtered and concentrated in vacuo to provide(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (0.6 g, crude): MS (ES)m/z 219 (M+H).

Step 1: Preparation of ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.17 g, 0.75 mmol) in diphenyl ether (0.1 mL), was added(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (0.18 g, 0.83 mmol). Themixture was subjected to microwave irradiation at 190° C. for 0.5 hours.After cooling to ambient temperature, the reaction mixture was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo. The crude material waspurified using flash chromatography (50% ethyl acetate/hexane) toprovide ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a thick liquid(0.035 g, 12% yield): MS (ES) m/z 407.2 (M+H).

Step 2: Preparation of ethyl4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.09 g, 0.2 mmol) in tetrahydrofuran (1 mL) was added palladium oncarbon (0.25 g, 50% wet w/w) and the mixture stirred under a hydrogenatmosphere at room temperature for 30 hours. The reaction waspartitioned between 50% methanol/ethyl acetate and filtered throughcelite. The filtrate was concentrated in vacuo to provide4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(crude 0.07 g, 100% yield): MS (ES) m/z 317.2 (M+H).

Step 3: Preparation of ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.07 g, 0.22 mmol) in dichloromethane (2 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.068 g, 0.4 mmol),1-hydroxybenzotriazole (0.05 g, 0.44 mmol), N,N-diisopropylethylamine(0.05 g, 0.4 mmol) and cyanoacetic acid (0.028 g, 0.33 mmol) and themixture was stirred at ambient temperature for 12 hours. The reactionwas quenched with water and extracted with dichloromethane. The organiclayer was washed with water, brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified using flash chromatography (6%methanol/dichloromethane) to provide ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.013 g, 5% yield): ¹H NMR (400 MHz, DMSO-d₆, at 90° C.) δ 11.58 (s,1H), 8.32 (s, 1H), 7.33 (s, 1H), 6.54 (br s, 1H) 4.28-4.29 (m, 2H)3.81-3.94 (m, 4H), 3.37-3.49 (m, 3H), 2.94 (s, 3H), 2.16 (m, 1H), 1.61(m, 2H), 1.30-1.33 (t, J=12 Hz, 3H), 0.94-0.96 (m, 3H); MS (ES) m/z384.2 (M+H).

Synthesis of Example 3: Preparation of ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Preparation of (3R,4R)-1-benzyl-4-methylpiperidin-3-amine

A solution of tert-butyl(3R,4R)-1-benzyl-4-methylpiperidin-3-yl)carbamate (2 g, 6.57 mmol) inHCl in dioxane (10 mL, 4M) was stirred at ambient temperature for 4hours. The reaction mixture was concentrated in vacuo and neutralizedwith triethylamine (7 mL). The residue was quenched with water andextracted with dichloromethane. The organic layer was washed with water,brine and dried over anhydrous sodium sulfate. The solution was filteredand concentrated in vacuo to provide (3R,4R)-1-benzyl-4-methylpiperidin-3-amine (1.3 g, crude): MS (ES) m/z 205.1(M+H).

Step 1: Preparation of ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(9 g, 40.17 mmol) in N-methyl-2-pyrrolidone (100 mL), was added(3R,4R)-1-benzyl-4-methylpiperidin-3-amine (9.8 g, 48.2 mmol) andtriethylamine (4.5 mL) in a sealed tube and the mixture was heated to170° C. for 16 hours. After cooling to room temperature, the reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (50% ethylacetate/hexane) to provide ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a semi solid (10 g, 64% yield): MS (ES) m/z 393.4 (M+H).

Step 2: Preparation of ethyl 4-(((3R, 4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(10 g, 25.5 mmol) in tetrahydrofuran (120 mL) was added palladium oncarbon (30 g, 50% wet w/w) and the mixture was stirred under a hydrogenatmosphere using a Parr-shaker (70 psi) at ambient temperature for 30hours. The reaction mixture was partitioned between 50% methanol/ethylacetate and filtered through celite. The filtrate was concentrated toprovide ethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(4.7 g, 95% yield): MS (ES) m/z 303.1 (M+H).

Step 3: Preparation of ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(4.7 g, 15.8 mmol) in dichloromethane (50 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (4.9 g, 31.6 mmol),1-hydroxylbenzotriazole (4.2 g, 31.7 mmol), N,N-diisopropylethylamine(12.2 mL, 31.6 mmol) and cyanoacetic acid (2.7 g, 31.7 mmol) and themixture was stirred at ambient temperature for 16 hours. The reactionwas quenched with water and extracted with dichloromethane. The organiclayer was washed with water, brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (6%methanol/dichloromethane) to provide ethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(3.8 g, 66% yield): ¹H NMR (400 MHz, DMSO-d₆ at 90° C.) δ 11.49 (s, 1H),8.79-8.81 (m, 1H), 8.56 (s, 1H), 7.16 (s, 1H) 6.64 (s, 1H) 4.27-4.36 (m,4H), 3.91 (m, 1H), 3.70 (m, 1H), 3.42 (m, 1H), 3.15 (m, 1H), 2.88 (m,1H), 2.14 (br s, 2H), 1.64 (m, 1H), 1.30-1.33 (t, J=8.75 Hz, 3H), 0.95(b s, 3H); MS (ES) m/z 370.3 (M+H).

Synthesis of Example 21: Preparation of 2-methoxyethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of 2-methoxyethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(4.0 g, 17.80 mmol) in methoxyethanol (40 mL) was added cesium carbonate(29.0 g, 89.0 mmol) and the mixture was stirred at ambient temperaturefor 16 hours. The reaction was quenched with water and extracted withethyl acetate. The organic layer was washed with water, brine and driedover anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (40% ethyl acetate/hexane) to provide 2-methoxyethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a white solid (2.6g, 57% yield): MS (ES) m/z 255 (M+H).

Step 2: Preparation of 2-methoxyethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of 2-methoxyethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.6 g, 2.35 mmol),(3R,4R)-1-benzyl-4-methylpiperidin-3-amine (0.48 g, 2.35 mmol) andtriethylamine (0.1 mL) in N-methyl-2-pyrrolidone (10 mL) in a sealedtube was heated to 140° C. for 12 hours. The reaction mixture was cooledto ambient temperature, quenched with water and extracted with ethylacetate. The organic layer was washed with water and brine and driedover anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (45% ethyl acetate/hexane) to provide 2-methoxyethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.35 g, 35% yield): MS (ES) m/z 423 (M+H).

Step 3: Preparation of 2-methoxyethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of 2-methoxyethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.35 g, 0.82 mmol) in tetrahydrofuran (10 mL) was added palladium oncarbon (0.3 g, 50% wet w/w) and the mixture was stirred under a hydrogenatmosphere at ambient temperature for 48 hours. The reaction mixture wasfiltered through celite. The filtrate was concentrated in vacuo toprovide2-methoxyethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(crude 0.16 g 58% yield): MS (ES) m/z 333 (M+H).

Step 4: Preparation of 2-methoxyethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of 2-methoxyethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.16 g, 0.48 mmol) in N,N-dimethylformamide (10 mL) was added1-ethyl-3-(3-dimethylamino propyl)carbodiimide.HCl (0.14 g, 0.96 mmol),1-hydroxybenzotriazole (0.13 g, 0.96 mmol), N,N-disopropylethylamine(0.25 mL, 1.44 mmol) and cyanoacetic acid (0.08 g, 0.96 mmol) and themixture was stirred at ambient temperature for 24 hours. The reactionmixture was partitioned between ethyl acetate and water and the organiclayer was separated. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (5% methanol/dichloromethane) to provide 2-methoxyethyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.03 g, 16% yield): ¹H NMR (400 MHz, DMSO-d₆, at 80° C.) δ 11.52 (s,1H), 8.74 (s, 1H), 8.57 (s, 1H), 7.16 (s, 1H) 6.65 (s, 1H) 4.34-4.36 (m,3H), 4.24 (m, 1H), 3.91 (m, 2H), 3.65-3.67 (m, 3H), 3.32 (s, 3H), 3.14(m, 1H), 2.15 (m, 1H), 1.56-1.65 (m, 3H), 0.95 (br s, 3H); MS (ES) m/z400 (M+H).

Synthesis of Example 24: Preparation of ethyl4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of ethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.1 g, 0.311 mmol), acrylonitrile (0.035 g, 0.66 mmol) andtriethylamine (0.13 mL, 0.99 mmol) in ethanol (10 mL) was heated at 70°C. for 2 hours. After cooling to ambient temperature, the reactionmixture was concentrated in vacuo and crude material purified usingflash chromatography (50% ethyl acetate/hexane) to provide ethyl4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.07 g, 63% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (br s, 1H), 9.08(d, J=9.2 Hz, 1H), 8.52 (s, 1H), 7.13 (s, 1H), 6.62 (s, 1H), 4.37 (br s,1H), 4.24-4.25 (m, 2H), 2.79 (d, J=8.8 Hz, 2H), 2.43-2.60 (m, 4H), 2.02(br s, 1H), 1.87 (br s, 1H), 1.70-1.55 (br s, 2H), 1.22-1.31 (m, 4H),0.85 (d, J=6.0 Hz, 3H); MS (ES) m/z 356.2 (M+H).

Synthesis of Example 34: Preparation of ethyl(R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step-1: Preparation of ethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.5 g, 2.23 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.53g, 2.67 mmol) and triethylamine (0.3 mL) in N-methyl-2-pyrrolidone (10mL) was subjected to microwave irradiation at 180° C. for 2 hours. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate. The solution was concentrated in vacuo. Thecrude material was purified by using flash chromatography (50% ethylacetate/hexane) to provide ethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.6 g, 35% yield): MS (ES) m/z: 389.2 (M+H).

Step 2: Preparation of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatehydrochloride Salt

To a solution of ethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.6 g, 1.17 mmol) in dichloromethane (15 mL) was added HCl in dioxane(2.0 mL, 4M) at 0° C. and the mixture was stirred at ambient temperaturefor 6 hours. The solution was concentrated in vacuo to provide ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HClas an off-white solid (0.3 g, crude): MS (ES) m/z: 289.2 (M+H).

Step 3: Preparation of ethyl(R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HClsalt (0.13 g, 0.45 mmol) in tetrahydrofuran:water (1:1, 2 mL:2 mL) wasadded N,N-diisopropylethylamine (0.2 mL, 0.92 mmol) followed by acryloylchloride (0.01 mL, 0.092 mmol) at 0° C. The mixture was stirred for 2hours. The reaction was quenched with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer was washedwith water, brine and dried over anhydrous sodium sulfate. The solutionwas filtered and concentrated in vacuo. The crude material was purifiedby using flash chromatography (ethyl acetate/hexane) to provide ethyl(R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.035 g, 22% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.68 (br s, 1H), 8.85 (br s, 1H), 8.53 (s, 1H), 7.19 (s, 1H), 6.75-6.82(m, 1H), 6.50-6.59 (m, 1H), 6.01-6.21 (m, 1H), 5.32-5.66 (m, 1H), 4.24(q, J=7.2 Hz, 2H), 4.11 (m, 1H), 3.72-3.84 (m, 1H) 3.57 (m, 1H), 2.06(m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 1.22-1.25(m, 1H), 0.82-1.09 (m, 1H); MS (ES) m/z: 343.2 (M+H).

Synthesis of Examples 68A and 68B: Preparation of enantiomers of(trans)-ethyl4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate68A and 68B

Chiral separation of(trans)-(rac)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoate

The enantiomers of(trans)-(rac)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoatewere separated by chiral chromatography.

Analytical Conditions:

Column: CHIRALPAK IA (250 mm×4.6 mm×51 m)

Mobile phase: nHexane:Ethanol with 0.1% DEA (50:50)

Flow rate: 1.0 mL/min

Enantiomer 1: Rentention time 4.161 min.

Enantiomer 2: Retention time 5.296 min.

Step 1: Preparation of(trans)-tert-butyl-(3-hydroxycyclopentyl)carbamate

To a solution of one of the enantiomers of(trans)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoate (1.2g, 3.42 mmol) in methanol (30 mL) was added potassium carbonate (0.71 g,5.14 mmol) and the mixture stirred at ambient temperature for 6 hours.The reaction mixture was concentrated in vacuo and the residue wasdissolved in water and extracted with ethyl acetate. The organic layerwas washed with water, brine and dried over anhydrous sodium sulfate.The solution was filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (30% ethyl acetate/hexane) toprovide tert-butyl-(3-hydroxycyclopentyl) carbamate as an off-whitesolid (0.42 g, 60.95% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 6.72 (br s,1H), 4.37 (d, J=3.6 Hz, 1H), 4.09-4.10 (m, 1H), 3.89-3.91 (m, 1H),1.75-1.91 (m, 2H), 1.66-1.70 (m, 1H), 1.44-1.51 (m, 1H), 1.35 (s, 9H),1.19-1.31 (m, 2H).

Step 2: Preparation of (trans)-3-(methylamino)cyclopentan-1-ol

To a solution of one of the enantiomers of(trans)-tert-butyl-(3-hydroxycyclopentyl)carbamate (0.15 g, 0.74 mmol)in tetrahydrofuran (5 mL) and was added lithium aluminium hydride (2.23mL, 2.23 mmol, (1.0M solution in tetrahydrofuran) dropwise at 0° C. andthe mixture was heated at 70° C. for 4 hours. After cooling, thereaction mixture was quenched with aqueous sodium hydroxide solution andethyl acetate and the suspension was filtered through celite. Theorganic layer was separated, washed with water and dried over anhydroussodium sulphate. The filtrate was concentrated in vacuo to provide3-(methylamino)cyclopentan-1-ol as a yellow oil (0.1 g, 80% yield): MS(ES) m/z 116 (M+H).

Step 3: Preparation of (trans)-ethyl4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo [2,3-b]pyridine-5-carboxylate

A solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.15 g, 0.66 mmol) and one of the enantiomers of3-(methylamino)cyclopentan-1-ol (0.092 g, 0.8 mmol) in dimethylsulfoxide (3 mL) was heated under microwave irradiation for 2 hours.After cooling to ambient temperature, the reaction mixture was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (9% methanol/dichloromethane) to obtainethyl4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (0.015 g, 7.42% yield).

Example 68A: (trans)-Ethyl4-((-3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, enantiomer 1

¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H), 8.20 (m, 1H), 7.24-7.26 (m,1H), 6.57-6.58 (m, 1H), 4.66-4.80 (m, 1H), 4.57 (m, 1H), 4.06-4.27 (m,3H), 2.82 (s, 3H), 1.78-1.96 (m, 3H), 1.60-1.76 (m, 2H), 1.48-1.50 (m,1H), 1.30 (t, J=8.8 Hz, 3H); MS (ES) m/z 304 (M+H).

Example 68B: (trans)-Ethyl4-((-3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,enantiomer 2

¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (br s, 1H), 8.20 (m, 1H), 7.24-7.26(m, 1H), 6.57-6.58 (m, 1H), 4.66-4.74 (m, 1H), 4.54-4.55 (m, 1H),4.20-4.27 (m, 3H), 2.78 (s, 3H), 1.80-1.94 (m, 3H), 1.71-1.78 (m, 2H),1.48-1.51 (m, 1H), 1.31 (t, J=8.8 Hz, 3H).

Synthesis of Example 69: Isolation of Trans enantiomer-2, (trans)-ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.24 (s, 1H), 7.26-7.28 (m,1H), 6.55-6.56 (m, 1H), 5.21-5.22 (m, 1H), 4.57-4.61 (m, 1H), 4.26 (q,J=6.8 Hz 2H), 3.94 (s, 2H), 2.84 (s, 3H), 2.11-2.20 (m, 2H), 1.92-2.0(m, 3H), 1.83-1.86 (m, 1H), 1.29 (t, J=7.6 Hz, 3H). Retention time:21.666 min.

Synthesis of Example 70: Isolation of Trans enantiomer-1, (trans)-ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.24 (s, 1H), 7.26-7.28 (m,1H), 6.55-6.56 (m, 1H), 5.21-5.22 (m, 1H), 4.57-4.61 (m, 1H), 4.25 (q,J=6.8 Hz, 2H), 3.94 (s, 2H), 2.82 (s, 3H), 2.10-2.11 (m, 2H), 1.85-1.96(m, 3H), 1.68-1.70 (m, 1H), 1.27 (t, J=7.2 Hz, 3H); Retention time:19.434 min.

Synthesis of Examples 72-75: Preparation of enantiomers of (trans)-ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate:72 and 75 and (trans)-ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate:73 and 74

Step-1: Preparation of (trans)-(rac)-3-aminocyclopentan-1-olhydrochloride Salt

To a solution of(trans)-(rac)-tert-butyl-(3-hydroxycyclopentyl)carbamate (0.27 g, 1.34mmol) in dichloromethane (5 mL) at 0° C. was added HCl in dioxane (4M, 5mL) and the solution warmed to ambient temperature and stirred for 5hours. The reaction mixture was concentrated in vacuo and the residuewashed with diethylether to provide 3-aminocyclopentan-1-olhydrochloride salt as a yellow oil (0.18 g, 96% yield): MS (ES) m/z 102(M+H).

Step-2: Preparation of (trans)-ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of (trans)-(rac)-ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.05 g, 0.22 mmol),3-amino cyclopentan-1-ol HCl (0.036 g, 0.26 mmol) and triethylamine(0.15 mL, 1.11 mmol) in dimethyl sulfoxide (3 mL) was heated undermicrowave irradiation at 150° C. for 1 hour. After cooling to ambienttemperature, the reaction mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (9% methanol/dichloromethane) to provide ethyl4-((3-hydroxycyclopentyl) amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.01 g, 17% yield): MS (ES) m/z 290 (M+H).

Step 3: Preparation of (trans)-(rac)-ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of (trans)-(rac)-ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.14 g, 0.48 mmol) in dichloromethane (10 mL) was added 2-cyanoaceticacid (0.062 g, 0.72 mmol), 4-dimethylaminopyridine (0.06 g, 0.48 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (0.14 g, 0.72mmol) and the mixture stirred at ambient temperature for 16 hours. Thereaction mixture was quenched with water and extracted withdichloromethane. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.035 g, 20% yield): MS (ES) m/z 357 (M+H).

Synthesis of Example 72: Isolation of Trans enantiomer-2, (trans)-ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo [2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (br s, 1H), 8.82 (d, J=7.6 Hz, 1H),8.52 (s, 1H), 7.17-7.18 (m, 1H), 6.67 (s, 1H), 4.61-4.63 (m, 2H),4.21-4.26 (m, 3H), 1.98-2.37 (m, 3H), 1.68-1.69 (m, 1H), 1.53 (m, 2H),1.29 (t, J=7.2 Hz, 3H). Retention time: 7.625 min.

Analytical Conditions:

Column: CHIRALPAK IA (250 mm×4.6 mm×51 m)

Mobile methanol with 0.1% DEA (50:50)

Flow rate: 0.5 mL/min

Synthesis of Example 73: Isolation of Trans enantiomer-1, (trans)-ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.81 (d, J=3.8 Hz, 1H), 8.53(s, 1H), 7.17 (s, 11H), 6.65 (s, 1H), 5.30 (br, 1H), 4.63-4.66 (m, 1H),4.25 (q, J=6.8 Hz, 2H), 3.99 (s, 2H), 2.05-2.31 (m, 3H), 1.93-2.0 (m,1H), 1.79-1.81 (m, 1H), 1.60-1.67 (m, 1H), 1.30 (t, J=6.8 Hz, 3H).Retention time: 9.484 min.

Analytical Conditions:

Column: CHIRALPAK IA (250 mm×4.6 mm×51 m)

Mobile methanol with 0.1% DEA (50:50)

Flow rate: 0.5 mL/min

Synthesis of Example 74: Isolation of Trans enantiomer-2, (trans)-ethyl4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) 11.70 (br s, 1H), 8.84 (d, J=7.2 Hz, 1H), 8.53(s, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 5.25 (br s, 1H), 4.63-4.67 (m, 1H),4.24 (q, J=7.2 Hz, 2H), 3.99 (s, 2H), 2.14-2.31 (m, 3H), 1.93-2.00 (m,1H), 1.80 (m, 1H), 1.63-1.65 (m, 1H), 1.33 (t, J=7.2 Hz, 3H). Retentiontime 4.846 min.

Analytical Conditions:

Column: CHIRALPAK IA (250 mm×4.6 mm×51 m)

Mobile methanol with 0.1% DEA (50:50)

Flow rate: 0.5 mL/min

Synthesis of Example 75: Isolation of Trans enantiomer-1, (trans)-ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.80 (d, J=7.6 Hz 1H), 8.51(s, 1H), 7.17 (s, 1H), 6.66 (s, 1H), 4.59-4.66 (m, 2H), 4.21-4.26 (m,3H), 2.23-2.31 (m, 1H), 2.05-2.10 (m, 1H), 1.93-2.04 (m, 1H), 1.64-1.69(m, 1H), 1.46-1.58 (m, 2H), 1.27 (t, J=7.6 Hz, 3H). Retention time:7.540 min.

Analytical Conditions:

Column: CHIRALPAK IA (250 mm×4.6 mm×51 m)

Mobile methanol with 0.1% DEA (50:50)

Flow rate: 0.5 mL/min

Synthesis of Example 92: Preparation of ethyl4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Preparation of ((1r,4r)-4-Aminocyclohexyl)methanol hydrochloride

To a stirred solution of tert-butyl((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (1 g, 17.47 mmol) indioxane (5 mL) was added 1,4-dioxane⋅hydrochloride (10 mL) at 0° C. andthe solution was stirred for 2 hours. The reaction was concentrated invacuo to provide crude (1r,4r)-4-aminocyclohexyl)methanol hydrochlorideas a semi solid (0.6 g crude).

Step 1: Preparation of ethyl4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3 g, 13.39 mmol) inN-methylpyrrolidine (10 mL) was added triethylamine (0.3 mL) and((1r,4r)-4-aminocyclohexyl)methanol hydrochloride (2.59 g, 19.9 mmol).The solution was heated in a sealed tube at 160° C. for 2 hours. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and extracted with dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulphate and concentrated invacuo. The crude material was purified by using flash chromatography(55% ethyl acetate/hexane) to provide ethyl4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (3 g, 71% yield): MS (ES) m/z 318.1 (M+H).

Step 2: Preparation of ethyl1-tosyl-4-(((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.5 g, 4.73 mmol) in dichloromethane (20 mL) were added triethylamine(1.2 mL, 12.08 mmol), 4-dimethylaminopyridine (0.28 g, 2.36 mmol) and4-toluenesulfonyl chloride (2.7 g, 14.19 mmol) at 0° C. The mixture wasstirred at room temperature for 12 hours at which time the reaction wasquenched with water and extracted with dichloromethane. The organiclayer was washed with brine, dried over anhydrous sodium sulphate andconcentrated in vacuo. The crude material was purified by using flashchromatography (55% ethyl acetate/hexane) to provide ethyl1-tosyl-4-(((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (1.6 g, 55% yield): MS (ES) m/z 626.1 (M+H).

Step-3: Preparation of ethyl4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl1-tosyl-4-(((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbo-xylate(1.6 g, 2.56 mmol) in dimethyl sulfoxide (5 mL) was added potassiumethanethioate (0.33 g, 2.89 mmol) and the mixture was stirred at 50° C.for 3 hours. The reaction mixture was cooled to ambient temperature andquenched with ice water. The obtained solid was filtered, washed withwater and dried to provide ethyl4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a white solid (1.6 g, 74%): MS (ES) m/z 530.1 (M+H).

Step 4: Preparation of((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo [2,3-b]pyridin-4-yl)amino)cyclohexyl) methanesulfonic acid

A solution of ethyl4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.3 g, 0.56 mmol) in hydrogen peroxide (0.15 mL) was treated withformic acid (0.8 mL) at 0° C. and the solution was stirred at roomtemperature for 2.5 hours. The reaction mixture was quenched with icewater, the obtained solid was filtered, washed with water and dried toprovide((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonicacid as a white solid (0.21 g, 66% yield): MS (ES) m/z 535.1 (M+H).

Step 5: Preparation of ethyl4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid (0.21 g, 0.39 mmol) in N,N-dimethylformamide (0.1mL) was added thionyl chloride (2.0 mL) at 0° C. and the solutionstirred at room temperature for 2.5 hours. The reaction mixture wasconcentrated in vacuo to provide ethyl4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a pale yellow solid (0.35 g crude).

Step 6: Preparation of ethyl4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.21 g, 0.37 mmol) in tetrahydrofuran (10 mL) was added methylamine (15mL, 2.0 M in tetrahydrofuran) and the solution was stirred in a sealedtube at room temperature 12 hours. The reaction mixture was quenchedwith water and extracted with ethyl acetate which was washed with brine,dried over anhydrous sodium sulphate, filtered and concentrated invacuo. The crude material was purified by flash column chromatography(40% ethyl acetate/hexane) to provide ethyl4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (0.07 g, 70% yield): MS (ES) m/z 548.1 (M+H).

Step 7: Preparation of ethyl4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.14 g, 0.25 mmol) in tetrahydrofuran (1 mL) was added potassiumtert-butoxide (0.07 g, 0.63 mmol) and the solution was stirred at roomtemperature for 2.5 hours. The reaction mixture was quenched with water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulphate, filtered and concentrated in vacuo. The crude materialwas purified by flash column chromatography (40% ethyl acetate/hexane)to provide ethyl4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off white solid (0.07 g, 37% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.63 (br s, 1H), 8.71-8.73 (m, 1H), 8.51 (s, 1H), 7.16 (s, 1H), 6.85(s, 1H), 6.51 (s, 1H), 4.22-4.24 (m, 2H), 3.87 (br s, 1H), 2.92-2.93 (m,2H), 2.55 (m, 3H), 2.11 (m, 2H), 1.97 (m, 2H), 1.84 (m, 2H), 1.29-1.30(m, 6H); MS (ES) m/z 382.1 (M+H).

Synthesis of Example 94: Preparation of ethyl4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Preparation of ((1r,4r)-4-(methylamino)cyclohexyl)methanol

To a stirred solution of tert-butyl((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (4 g, 17.47 mmol) intetrahydrofuran (75 mL) was added lithium aluminium hydride (26 mL, 26.2mmol, 1 M solution in tetrahydrofuran) slowly at 0° C. and the mixturewas slowly heated at 60° C. for 12 hours. The reaction mixture wascooled to room temperature and quenched with ethyl acetate and filteredthrough celite. The organic layer was washed with water, brine, driedover anhydrous sodium sulphate, filtered and concentrated in vacuo toprovide ((1r,4r)-4-(methylamino)cyclohexyl)methanol as a yellow solid (3g crude): MS (ES) m/z 144.1 (M+H).

Step 1: Preparation of ethyl4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(3 g, 13.39 mmol) in diphenyl ether (10 mL) was added((1r,4r)-4-(methylamino)cyclohexyl)methanol (3.4 g, 24.10 mmol) and thesolution was subjected to microwave irradiation at 180° C. for 2 hours.The reaction mixture was cooled to ambient temperature, quenched withwater and extracted with dichloromethane. The organic layer was washedwith brine, dried over sodium sulphate, filtered and concentrated invacuo. The crude material was purified by using flash chromatography(55% ethyl acetate/hexane) to provide ethyl4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (1 g, 27% yield): MS (ES) m/z 332.2 (M+H).

Step 2: Preparation of ethyl4-(methyl((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.0 g, 3.02 mmol) in dichloromethane (20 mL) was added triethylamine(1.2 mL, 12.08 mmol) at 0° C., followed by 4-dimethylaminopyridine (0.18g, 1.51 mmol) and 4-toluenesulfonyl chloride (1.7 g, 9.06 mmol). Themixture was stirred under a N₂ atmosphere at room temperature for 12hours. The reaction mixture was quenched with water and extracted withdichloromethane. The organic layer was washed with brine, dried overanhydrous sodium sulphate, filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (20% ethylacetate/hexane) to provide ethyl4-(methyl((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (1.4 g, 73% yield): MS (ES) m/z 640.2 (M+H).

Step 3: Preparation of ethyl4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-(methyl((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.4 g, 2.18 mmol) in dimethyl sulfoxide (30 mL) was added potassiumethanethioate (0.28 g, 2.47 mmol) and the mixture was stirred at 50° C.for 3 hours. The reaction mixture was quenched with ice water, theobtained solid was filtered, washed with water and dried to provideethyl4-(((1r,4r)-4-((acetylthio)-methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown colour solid (1.0 g, 84% yield): MS (ES) m/z 544.2 (M+H).

Step 4: Preparation of((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonic acid

A stirred solution of ethyl4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.1 g, 2.02 mmol) in hydrogen peroxide (1 mL) was treated with formicacid (9 mL) at 0° C. and the solution was stirred at room temperaturefor 2.5 hours. The reaction mixture was quenched with ice water, theobtained solid was filtered, washed with water and dried to obtain((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonicacid as an off-white solid (0.55 g, 50% yield): ¹HNMR (400 MHz, DMSO-d₆)δ 8.21 (s, 1H), 7.9 (d, J=7.6 Hz, 2H), 7.7 (d, J=5.2 Hz, 1H), 7.39 (d,J=8 Hz, 2H), 6.67 (d, J=3.2 Hz, 1H), 4.25-4.18 (q, 2H), 3.64-3.60 (m,2H), 2.75 (s, 3H), 2.37-02.32 (m, 5H), 2.06-2.03 (m, 2H), 1.75-1.70 (m,5H), 1.29 (t, J=6.8 Hz, 3H), 1.06-0.96 (m, 2H).

Step 5: Preparation of ethyl4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)-methanesulfonicacid (0.5 g, 0.9 mmol) in N,N-dimethylformamide (0.5 mL) was addedthionyl chloride (5 mL) at 0° C. and the solution stirred for 2.5 hours.The reaction mixture was concentrated in vacuo to provide ethyl4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a colorless liquid (0.35 g crude): MS (ES) m/z 568.2 (M+H).

Step 6: Preparation of ethyl4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.35 g, 0.61 mmol) in tetrahydrofuran (10 mL) was added methylamine (15mL, 2.0 M in tetrahydrofuran) and the solution was stirred for 12 hoursat room temperature. The reaction mixture was quenched with water andextracted with ethyl acetate, brine, dried over anhydrous sodiumsulphate and concentrated in vacuo. The crude material was purified byusing flash chromatography (40% ethyl acetate/hexane) to provide ethyl4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow solid (0.300 g, 87%): MS (ES) m/z 563.2 (M+H).

Step 7: Preparation of ethyl4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.3 g, 0.53 mmol) in tetrahydrofuran (8 mL) was added potassiumtert-butoxide (0.15 g, 1.33 mmol) and the solution was stirred at roomtemperature for 1.5 hours. The reaction mixture was quenched with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulphate and concentrated in vacuo.The crude material was purified by using flash chromatography (45% ethylacetate/hexane) to provide ethyl4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.08 g, 37% yield): ¹H NMR (400 MHz, DMSO-d₆): δ11.64 (s, 1H), 8.18 (s, 1H), 7.25 (s, 1H), 6.85 (d, J=4.8 Hz, 1H), 6.40(s, 1H), 4.25-4.20 (q, 2H), 3.81 (bs, 1H), 2.90 (d, J=5.6 Hz, 2H), 2.80(s, 3H), 2.55 (d, J=4.8 Hz, 3H), 2.05-2.02 (m, 2H), 1.81-1.76 (m, 5H),1.29 (t, J=6.8 Hz, 3H), 1.21-1.19 (m, 2H); MS (ES) m/z 409.0 [M+H].

Synthesis of Example 113: Preparation of ethyl4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of 3-aminocyclopentan-1-ol trifluoroacetic acid Salt

To a solution of tert-butyl (3-hydroxycyclopentyl)carbamate (1.0 g, 5.47mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL).The solution was stirred at ambient temperature for 5 hours and thenconcentrated in vacuo to dryness to provide 3-aminocyclopentan-1-oltrifluoroacetic acid salt (1.17 g, crude).

Step 2: Preparation of ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A stirred solution of ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.27 g, 5.44 mmol),3-aminocyclopentan-1-ol trifluoroacetic acid salt (1.17 g, 5.44 mmol),triethylamine (2.27 g, 16.3 mmol) in N-methyl-2-pyrrolidone (10 mL) washeated in a sealed tube at 160° C. for 12 hours. After cooling toambient temperature, the reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (10% methanol/dichloromethane) to provide ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a colorless gum (0.82 g, 50% yield): MS (ES) m/z 290.1 (M+H).

Step 3: Preparation of ethyl4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a suspension of potassium carbonate (0.86 g, 6.25 mmol) in ethanol(10 mL) was added ethyl4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.74 g, 2.56 mmol) and the mixture was stirred at ambient temperaturefor 0.5 hours. Then acrylonitrile (1.35 g, 25.6 mmol) was added and themixture was stirred for 15 hours. The solvent was concentrated in vacuoand residue was partitioned between ethyl acetate and water. The organiclayer was washed with water, brine and dried over anhydrous magnesiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified by reverse phase preparative HPLC (0.1% ammonia inwater:acetonitrile) to provide ethyl4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.05 g, 6% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (br s, 1H), 8.95(d, J=7.6 Hz, 1H), 8.50 (s, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 4.59-4.5(m, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.02-4.10 (m, 1H), 3.56-0.351 (m, 2H),2.73 (t, J=6.4 Hz, 2H), 2.26-2.19 (m, 1H), 2.15-2.07 (m, 1H), 1.90-1.82(m, 2H), 1.73-1.69 (m, 2H), 1.29 (t, J=6.2 Hz, 3H); MS (ES) m/z 343.1(M+H).

Prep HPLC Analytical Conditions

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% Ammonia in water

Mobile phase (B): ACN

Flow rate: 1.0 mL/min

Retention time: 12.61 min.

Synthesis of Example 117: Preparation of ethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of ethyl(R)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(5 g, 22.3 mmol) in N-methyl-2-pyrrolidone (35 mL), was added(R)-1-benzylpiperidin-3-amine (8.48 g, 44.6 mmol) and triethylamine (1mL) in a sealed tube. The mixture was heated to 170° C. for 16 hours.After cooling to room temperature the reaction mixture was quenched withwater to precipitate a solid which was filtered and washed with water,dried and concentrated in vacuo to provide ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (8 g, 95% yield): MS (ES) m/z 379.1 (M+H).

Step 2: Preparation of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.25 g, 0.66 mmol) in methanol (5 mL) was added 10% palladium on carbon(0.3 g, 50% wet w/w) and the mixture was stirred under a hydrogenatmosphere at ambient temperature for 12 hours. The reaction mixture waspartitioned between 50% methanol/ethyl acetate and filtered throughcelite. The filtrate was concentrated in vacuo to provide ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate asan off-white solid (0.1 g, 90% yield): MS (ES) m/z 289.3 (M+H).

Step 3: Preparation of ethyl(R)-4-((l-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (9g, 31.3 mmol) in dichloromethane (50 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (9.7 g, 62.5 mmol),1-hydroxybenzotriazole (8.43 g, 62.5 mmol), N,N-diisopropylethylamine(11.3 mL, 62.5 mmol) and cyanoacetic acid (0.76 g, 9.0 mmol) and themixture was stirred at ambient temperature for 18 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by using flash chromatography (5%methanol/dichloromethane) to provide ethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(7.5 g, 68% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.68 (br s, 1H),8.86-8.79 (m, 1H), 8.54 (s, 1H), 7.20 (s, 1H), 6.67 (s, 1H), 4.17-4.44(m, 3H), 3.70-4.05 (m, 4H), 3.45-3.48 (m, 1H), 3.11-3.24 (m, 1H), 2.06(br s, 1H), 1.57-1.72 (m, 3H), 1.28-1.32 (t, J=7.2 Hz, 3H); MS (ES) m/z356.1 (M+H).

Synthesis of Example 118: Preparation of methyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a solution of ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.1 g, 0.25 mmol) in methanol (10 mL) was added lithium hydroxide(0.017 g, 0.75 mmol) and the mixture was heated to 60° C. for 10 hours.After cooling to ambient temperature, the reaction mixture wasconcentrated in vacuo to dryness. The residue was dissolved in water andacidified with 2N hydrochloric acid and the aqueous mixture wasextracted with ethyl acetate. The organic layer was washed with water,brine and dried over anhydrous sodium sulfate. The solution was filteredand concentrated in vacuo to provide4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (0.085 g, 91% yield): MS (ES) m/z 365.2 (M+H)

Step 2: Preparation of ethyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (0.08 g, 0.22 mmol) in methanol (10 mL) was added sulfuric acid(1.0 mL) and the solution was heated to 80° C. for 48 hours. Aftercooling to ambient temperature, the reaction was quenched with saturatedbicarbonate solution and extracted with ethyl acetate. The organic layerwas washed with water, brine and dried over anhydrous sodium sulfate.The solution filtered and concentrated in vacuo to provide methyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.1 g, crude): MS (ES) m/z 379.1 (M+H).

Step 3: Preparation of methyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of methyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.1 g, 0.34 mmol) in tetrahydrofuran (5 mL), was added palladium oncarbon (0.5 g, 50% wet w/w) and the mixture was stirred under a hydrogenatmosphere at ambient temperature for 12 hours. The resulting solutionwas partitioned between 50% methanol/ethyl acetate and filtered throughcelite. The filtrate was concentrated in vacuo to provide methyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.09 g, 93% yield): MS (ES) m/z 289.2 (M+H).

Step 4: Preparation of methyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of methyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.1 g, 0.34 mmol) in dichloromethane (5 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.10 g, 0.69 mmol),1-hydroxybenzotriazole (0.09 g, 0.69 mmol), N,N-diisopropylethylamine(0.89 g, 6.94 mmol) and cyanoacetic acid (0.04 g, 0.52 mmol) and themixture was stirred at ambient temperature for 12 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (6%methanol/dichloromethane) to provide methyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methypiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.06 g,49% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.73 (m, 1H), 8.82-8.91 (m,1H), 8.52-8.55 (m, 1H), 7.19-7.22 (m, 1H), 6.65-6.70 (m, 1H), 4.26-4.42(m, 2H), 4.06 (s, 1H), 3.85 (s, 1H), 3.65-3.68 (m, 1H), 3.38-3.42 (m,1H), 3.04-3.19 (m, 2H), 2.18-2.88 (m, 1H), 2.12 (br s, 1H), 1.35-1.64(m, 3H), 0.88-0.96 (m, 3H); MS (ES) m/z 356 (M+H).

Examples 119 and 120: Preparation of tert-butyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateand4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid trifluoroacetic acid Salt

Step 1: Preparation of tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of 4-chloro-H-pyrrolo[2,3-b]pyridine-5-carboxylic acid(3.5 g, 17.8 mmol) in toluene (20 mL), was addedN-(di-tert-butoxymethyl)propan-2-amine (14.5 g, 71.4 mmol) and themixture was heated to 100° C. for 1 hour and then stirred at ambienttemperature for 12 hours. The reaction mixture was quenched with waterand extracted with ethyl acetate. The organic layer was washed withwater, brine and dried over anhydrous sodium sulfate. The solution wasfiltered and concentrated in vacuo to provide tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.1 g, 63% yield): MS(ES) m/z 253.1 (M+H).

Step 2: Preparation of tert-butyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.9 g, 3.57 mmol) inN-methylpyrrolidine (2 mL), was added(3R,4R)-1-benzyl-4-methylpiperidin-3-amine (0.72 g, 3.57 mmol) andtriethylamine (0.2 mL) in a sealed tube and the mixture heated at 170°C. for 16 hours. After cooling to ambient temperature, the reactionmixture was quenched with water to precipitate a solid. The solid wasfiltered, washed with water and dried to provide tert-butyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (1 g, 67% yield): MS (ES) m/z 421.2 (M+H).

Step 3: Preparation of tert-butyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of tert-butyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.4 g, 0.95 mmol) in tetrahydrofuran (1 mL) was added palladium oncarbon (1 g, 50% wet w/w) and the mixture was stirred under a hydrogenatmosphere at ambient temperature for 24 hours. The reaction waspartitioned between 50% methanol/ethyl acetate and filtered throughcelite. The filtrate was concentrated in vacuo to provide tert-butyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.4 g, crude): MS (ES) m/z 331.2 (M+H).

Step 4: Preparation of Example 119: tert-butyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of tert-butyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.4 g, 1.2 mmol) in dichloromethane (10 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.37 g, 2.4 mmol),1-hydroxyl benzotriazole (0.32 g, 2.4 mmol), N,N-diisopropylethylamine(0.31 g, 0.24 mmol) and cyanoacetic acid (0.2 g, 2.4 mmol) and themixture was stirred at ambient temperature for 12 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (10%methanol/dichloromethane) to provide tert-butyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 41% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 11.65-11.71 (m, 1H), 8.91-8.93 (m, 1H),8.48-8.52 (m, 1H), 7.17-7.20 (m, 1H) 6.63-6.69 (s, 1H) 4.21-4.43 (m,2H), 3.84-4.07 (m, 2H), 3.60-3.70 (s, 1H), 3.38-3.41 (m, 1H), 3.07-3.20(m, 2H), 2.13 (br s, 1H), 1.61-1.68 (m, 1H), 1.54 (s, 9H), 0.90-0.96 (m,3H); MS (ES) m/z 398.2 (M+H).

Step 5: Preparation of Example 120:4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid trifluoroacetic acid Salt

To a solution of tert-butyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.055 g, 1.2 mmol) was added trifluoroacetic acid (1 mL) and themixture was stirred at ambient temperature for 1.5 hours. The reactionwas concentrated in vacuo and crude material was purified by reversephase preparative HPLC to provide4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid.trifluoroacetic acid salt (0.03 g, 47.6% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 12.37 (br s, 1H), 9.94 (br s, 1H), 8.62 (s, 1H), 7.38 (m, 1H)6.93 (m, 1H) 4.31-4.54 (m, 2H), 3.69-4.11 (m, 2H), 3.69-3.73 (m, 1H),3.41-3.49 (m, 1H), 3.10-3.19 (m, 1H), 2.15 (br s, 1H), 1.62-1.70 (m,1H), 1.46-1.49 (m, 1H), 1.21-1.36 (m, 1H), 0.85-0.94 (m, 3H); MS (ES)m/z 342.3 (M+H). Retention time: 4.603 min.

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% TFA in water

Mobile phase (B): ACN,

Flow rate: 1.0 mL/min

Synthesis of Example 121: Preparation of(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid trifluoroacetic acid Salt

Step 1: Preparation of tert-butyl(R)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, 11.9 mmol) inN-methylpyrrolidine (1 mL), was added (R)-1-benzylpiperidin-3-amine(0.08 g, 23.8 mmol) and triethylamine (0.01 mL). The mixture was heatedin a sealed at 170° C. for 16 hours. After cooling to ambienttemperature, the reaction was quenched with water to precipitate asolid. The solid was filtered, washed with water and dried to providetert-butyl(R)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (0.1 g, crude): MS (ES) m/z 407.2 (M+H).

Step 2: Preparation of tert-butyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution tert-butyl(R)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(3.1 g, 7.63 mmol) in methanol (10 mL) was added palladium on carbon (2g, 50% wet w/w) and the mixture was stirred under a hydrogen atmosphereusing Parr-shaker (70 psi) at ambient temperature for 30 hours. Thereaction mixture was filtered through celite and washed with 50%methanol/ethyl acetate (200 mL). The filtrate was concentrated in vacuoto provide tert-butyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.0g crude): MS (ES) m/z 317.1 (M+H)

Step 3: Preparation of tert-butyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of tert-butyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.0g, 6.32 mmol) in dichloromethane (20 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (1.07 g, 12.6 mmol),1-hydroxybenzotriazole (1.70 g, 12.6 mmol), N,N-diisopropylethylamine(2.4 g, 18.9 mmol) and cyanoacetic acid (1.70 g, 12.6 mmol) and mixturewas stirred at ambient temperature for 12 hours. The reaction mixturewas quenched with water and extracted with dichloromethane. The organiclayer was washed with water, brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified using flash chromatography (10%methanol/dichloromethane) to provide tert-butyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.4 g,58% yield): MS (ES) m/z 384.1 (M+H).

Step 4: Preparation of(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid trifluoroacetic acid Salt

To tert-butyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1 g, 2.6 mmol) was added trifluoroacetic acid (5 mL) and the mixturewas stirred at ambient temperature for 1.5 hours. The reaction wasconcentrated in vacuo and crude material was purified using reversephase preparative HPLC (0.1% trifluoroacetic acid in water/methanol) toprovide (R)-4-((1-(2-cyanoacetyl) piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid trifluoroacetic acidsalt (0.72 g, 63% yield): ¹H NMR (400 MHz, D₂O, DMSO-d₆) δ 8.59 (s, 1H),7.32-7.34 (m, 1H) 6.81-6.86 (m, 1H) 4.40 (m, 1H), 4.23 (m, 1H),3.90-4.05 (m, 2H), 3.33-3.48 (m, 2H), 2.04 (m, 1H), 1.57-1.78 (m, 3H),1.18-1.21 (m, 1H); MS (ES) m/z 328.1 (M+H).

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic);

Mobile phase (A): 0.1% TFA in water

Mobile phase (B): Methanol;

Flow rate: 1.0 mL/min

Synthesis of Example 123: Preparation of ethyl(R)-4-((1-(2-cyanoethyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HCl(0.07 g, 0.21 mmol), acrylonitrile (0.11 g, 2.16 mmol) and triethylamine(0.06 mL, 0.42 mmol) in ethanol (3 mL) was heated to 80° C. for 2 hours.After cooling to ambient temperature, the solvent was concentrated invacuo and the crude material purified using flash chromatography (5%methanol/dichloromethane) to provide ethyl(R)-4-((1-(2-cyanoethyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.025 g, 34% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.64 (s, 1H), 8.93 (b, 1H), 8.52 (s, 1H), 7.15 (s, 1H), 6.55 (s, 1H),4.16-4.25 (m, 3H), 2.90-2.88 (m, 1H), 2.64 (s, 3H), 2.53-2.61 (m, 2H),2.31-2.38 (m, 2H), 1.83-1.92 (m, 1H), 1.63-1.75 (m, 1H), 1.43-1.62 (m,2H), 1.28-1.38 (m, 3H); MS (ES) m/z 342.1 (M+H).

Synthesis of Example 124: Preparation of isopropyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of isopropyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid(0.5 g, 2.55 mmol) in isopropyl alcohol (20 mL) was added concentratedsulfuric acid (0.2 mL) at 0° C. and the mixture heated at reflux for 10hours. After cooling to ambient temperature, the reaction wasconcentrated in vacuo and the residue was quenched with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with water, brine and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo to provide isopropyl4-chloro-1H-pyrrolo [2,3-b]pyridine-5-carboxylate as a white solid (0.45g, crude): MS (ES) m/z: 239.1 (M+H).

Step 2: Preparation of isopropyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of isopropyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.4 g, 1.68 mmol), (3R,4R)-1-benzyl-4-methylpiperidin-3-amine (0.41 g,2.01 mmol) and triethylamine (0.5 mL) in N-methyl-2-pyrrolidone (5 mL)was subjected to microwave irradiation at 180° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate. The solution wasfiltered and concentrated in vacuo. The crude material was purified byusing flash chromatography (ethyl acetate/hexane) to provide isopropyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a liquid (0.6 g, 88% yield): MS (ES) m/z: 407.1 (M+H).

Step 3: Preparation of isopropyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of isopropyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.6 g, 1.47 mmol) in tetrahydrofuran (30 mL) was added palladium oncarbon (0.9 g, 50% wet w/w) and the mixture was stirred under hydrogenatmosphere (70 psi) by using Parr-shaker at ambient temperature for 16hours. The reaction mixture was filtered through celite and filtrate wasconcentrated in vacuo to provide isopropyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.45 g crude): MS (ES)hn/z: 317.1 (M+H).

Step 4: Preparation of isopropyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of isopropyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 0.63 mmol) in dichloromethane (6 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.14 g, 0.75 mmol),1-hydroxybenzotriazole (0.1 g, 0.75 mmol), N,N-diisopropylethylamine(0.3 mL, 1.58 mmol) and cyanoacetic acid (0.08 g, 0.94 mmol) and themixture was stirred at ambient temperature for 6 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (ethylacetate/hexane) to provide isopropyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a paleyellow solid (0.05 g, 21% yield). ¹H NMR (400 MHz, DMSO-d₆, at 90° C.) δ11.54 (br s, 1H), 8.85 (d, J=8.4 Hz, 1H), 8.54 (s, 1H), 7.17 (s, 1H),6.64 (br s, 1H), 5.12-5.18 (m, 1H), 4.25-4.42 (m, 2H), 3.88-4.00 (m,1H), 3.68-3.79 (m, 1H), 3.28-3.44 (m, 1H), 2.65-2.87 (m, 1H), 2.07-2.17(m, 1H), 1.57-1.66 (m, 2H), 1.43-1.48 (m, 1H), 1.32 (t, J=6.4 Hz, 6H),0.96 (br s, 3H); MS (ES) m/z 384.3 (M+H).

Synthesis of Example 125: Preparation of propyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a suspension of sodium hydride (0.53 g, 13.39 mmol) indimethylformamide (30 mL) was added ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.0 g, 8.92 mmol) at0° C. and the mixture was stirred for 30 minutes. Then2-(trimethylsilyl)ethoxymethyl chloride (1.9 mL, 10.7 mmol) was added at0° C. and the mixture stirred for 2 hours. The reaction mixture wasquenched with ice water and extracted with ethyl acetate. The combinedorganic layer was washed with water, brine and dried over sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (ethylacetate/hexane) to provide ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a liquid (2.0 g, 64% yield): MS (ES) m/z 355.1 (M+H).

Step 2: Preparation of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a solution of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.8, 5.07 mmol) in methanol:water (8:2, 30 mL) at 0° C. was addedsodium hydroxide (0.45 g, 10.1 mmol). The mixture was then heated at 70°C. for 10 hours. After cooling to ambient temperature, the reactionmixture was concentrated in vacuo and residue was dissolved in water andacidified with 3N HCl. The aqueous layer was extracted with ethylacetate. The organic layer was washed with water, brine and dried overanhydrous sodium sulfate. The solution was filtered and concentrated invacuo to provide4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as an off-white solid (1.5 g, crude): MS (ES) m/z: 327.1 (M+H).

Step 3: Preparation of propyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (0.5 g, 1.53 mmol) in N,N dimethylformamide (10 mL) was addedpotassium carbonate (0.42 g, 3.06 mmol) and 1-iodopropane (0.3 mL, 6.12)and the mixture was stirred at room temperature for 16 hours. Thereaction was quenched with ice water and extracted with ethyl acetate.The organic layer was washed with water, brine and dried over sodiumsulfate. The solution was filtered and concentrated in vacuo to providepropyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a liquid (0.6 g, crude): MS (ES) m/z: 369.1 (M+H).

Step 4: Preparation of propyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A mixture of propyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 0.54 mmol), (3R,4R)-1-benzyl-4-methylpiperidin-3-amine (0.13 g,0.65 mmol) and triethylamine (0.1 mL, xx mmol) in N-methyl-2-pyrrolidone(6.0 mL) was heated in a sealed tube for 12 hours. After cooling toambient temperature, the reaction was quenched with water and extractedwith ethyl acetate. The organic layer was washed with water, brine anddried over sodium sulfate. The solution was filtered and concentrated invacuo. The crude material was purified using flash chromatography (ethylacetate/hexane) to provide propyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a liquid (0.8 g, 69% yield): MS (ES) m/z: 537.3 (M+H).

Step 5: Preparation of propyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of propyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.8 g, 1.49 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (10 mL) and the mixture was stirred at ambient temperature for 3hours. The volatiles were removed in vacuo and residue was dissolveddichloromethane (10 mL) and ethylenediamine (10 mL) was added. Thereaction was stirred at ambient temperature for 3 hours. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo. The crude material was purified by using flash chromatography(ethyl acetate/hexane) to provide propyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a pale yellow solid (0.45 g, 75% yield): MS (ES) m/z: 407.3 (M+H).

Step 6: Preparation of propyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of propyl4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.45 g, 1.18 mmol) in tetrahydrofuran (50 mL) was added palladium oncarbon (0.5 g, 50% wet w/w) and the mixture was stirred under a hydrogenatmosphere at ambient temperature for 10 hours. The reaction mixture wasfiltered through celite. The filtrate was concentrated in vacuo toprovide propyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.3 g, crude): MS (ES) m/z: 317.4 (M+H).

Step 7: Preparation of propyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of propyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.15 g, 0.47 mmol) in dichloromethane (5 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.108 g, 0.56 mmol),1-hydroxybenzotriazole (0.08 g, 0.56 mmol), N,N-diisopropylethylamine(0.2 mL, 1.18 mmol), cyanoacetic acid (0.06 g, 0.71 mmol) and themixture was stirred at ambient temperature for 16 hours. The reactionwas quenched with water and extracted with dichloromethane. The organiclayer was washed with water, brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified using flash chromatography (ethyl acetate/hexane)to provide propyl4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a pale yellow solid (0.07 g, 42% yield): ¹H NMR (400 MHz, DMSO-d₆, at90° C.) δ 11.47 (br s, 1H), 8.81 (d, J=6.8 Hz, 1H), 8.57 (s, 1H), 7.16(s, 1H), 6.64 (br s, 1H), 4.38 (m, 1H), 4.20-4.21 (m, 3H), 3.70-3.84 (m,2H), 3.38-3.40 (m, 1H), 3.16 (m, 1H), 2.15 (m, 1H), 1.68-1.77 (m, 3H),1.52-1.64 (m, 1H), 1.07-1.24 (m, 1H), 0.95-0.99 (br s, 6H); MS (ES) m/z:384 (M+H).

Synthesis of Example 126: Preparation of ethyl4-(((3R,4R)-1-(1-cyanocyclopropane-1-carbonyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.15 g, 0.49 mmol) in dichloromethane (6 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.142 g, 0.74 mmol),1-hydroxybenzotriazole (0.1 g, 0.74 mmol), N,N-diisopropylethylamine(0.3 mL, 1.48 mmol), 1-cyanocyclopropane-1-carboxylic acid (0.08 g, 0.74mmol) and the mixture was stirred at room temperature for 10 hours. Thereaction was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by using flash chromatography (10%methanol/dichloromethane) to provide ethyl4-(((3R,4R)-1-(1-cyanocyclopropane-1-carbonyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b] pyridine-5-carboxylate as anoff-white solid (0.05 g, 26% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.69(br s, 1H), 8.87 (d, J=8.4 Hz, 1H), 8.52 (s, 1H), 7.19 (s, 1H), 6.68 (brs, 1H), 4.41 (m, 2H), 4.20-4.28 (m, 3H), 3.28 (s, 3H), 2.16 (m, 1H),1.68 (m, 1H), 1.46 (m, 3H), 1.21-1.29 (m, 4H), 0.93 (d, J=5.6 Hz, 3H);MS (ES) m/z: 396 (M+H).

Synthesis of Example 127: Preparation of ethyl4-(((3R,4R)-1-(2-cyanopropanoyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.15 g, 0.49 mmol) in dichloromethane (6 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (0.142 g, 0.74 mmol),1-hydroxybenzotriazole (0.1 g, 0.74 mmol), N,N-diisopropylethylamine(0.3 mL, 1.48 mmol) and 2-cyanopropanoic acid (0.075 g, 0.74 mmol) andthe mixture was stirred at room temperature for 10 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by using flash chromatography (ethylacetate/hexane) to provide ethyl4-(((3R,4R)-1-(2-cyanopropanoyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.038 g, 20% yield): ¹H NMR (400 MHz, DMSO-d₆, at90° C.) δ 11.47 (br s, 1H), 8.82 (d, J=8.4 Hz, 1H), 8.55 (s, 1H), 7.15(s, 1H), 6.65 (br s, 1H), 4.40 (m, 2H), 4.27 (m, 3H), 3.89 (m, 1H),3.0-3.31 (m, 2H), 2.15 (m, 1H), 1.67 (m, 1H), 1.49 (m, 1H), 1.24-1.32(m, 6H), 0.94 (d, J=6.0 Hz, 3H); MS (ES) m/z: 384.4 (M+H).

Synthesis of Example 128: Preparation of ethyl(R)-4-((1-(1-cyanocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HCl(0.07 g, 0.24 mmol) in dichloromethane (5 mL) was addeddiisopropyethylamine (0.12 mL, 0.72 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (0.06 g, 0.36 mmol),1-hydroxybenzotriazole (0.04 g, 0.36 mmol) and1-cyanocyclopropane-1-carboxylic acid (0.04 g, 0.36 mmol) and themixture was stirred at ambient temperature for 12 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Thecombined organic layers were washed with water, brine and dried overanhydrous sodium sulfate. The solution was filtered and concentrated invacuo. The crude material was purified using flash chromatography (100%ethyl acetate/hexane). The impure product was further purified by prepHPLC to provide ethyl(R)-4-((1-(1-cyanocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.022 g, 26% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.69 (s, 1H), 8.86 (d, J=6.8 Hz, 1H), 8.54 (s, 1H), 7.20 (s, 1H), 6.68(s, 1H), 4.24 (d, J=6.8 Hz, 3H), 3.96 (d, J=11.2 Hz, 1H), 3.69 (br s,3H), 2.06 (br s, 1H), 1.76 (br s, 3H), 1.55 (br s, 3H), 1.22-1.31 (m,4H); MS (ES) m/z 382.3 (M+H).

Retention time: 13.605 min.

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic);

Mobile phase (A): 0.1% Ammonia in water;

Mobile phase (B): ACN; Flow rate: 1.0 mL/min.

Synthesis of Example 129: Preparation of ethyl4-(((3R)-1-(2-cyanopropanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HCl(0.06 g, 0.20 mmol) in dichloromethane (5 mL) was addeddiisopropyethylamine (0.10 mL, 0.62 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (0.059 g, 0.31 mmol),1-hydroxybenzotriazole (0.042 g, 0.31 mmol) and 2-cyanopropanoic acid(0.030 g, 0.31 mmol). The mixture was stirred at ambient temperature for12 hours. The reaction was quenched with water and extracted withdichloromethane. The combined organic layers were washed with water,brine and dried over anhydrous sodium sulfate. The solution was filteredand concentrated in vacuo. The crude material was further purified byprep HPLC to provide ethyl4-(((3R)-1-(2-cyanopropanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.016 g, 23% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.68 (s, 1H), 8.83-8.89 (m, 1H), 8.53 (s, 1H), 7.19 (s, 1H), 6.66 (s,1H), 4.37-4.42 (m, 1H), 4.17-4.24 (m, 2H), 4.09-4.11 (m, 2H), 3.77-3.79(m, 1H), 3.42-3.58 (m, 3H), 2.04 (br s, 1H), 1.51-1.71 (m, 3H),1.38-1.40 (m, 2H), 1.27-1.33 (m, 3H); MS (ES) m/z 370.2 (M+H).

Retention time: 9.050 min

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic);

Mobile phase (A): 0.1% Ammonia in water

Mobile phase (B): ACN; Flow rate: 1.0 mL/min.

Synthesis of Example 130: Preparation of propyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of propyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(10.0 g, 44.51 mmol) in propanol (100 mL), was added cesium carbonate(43.4 g, 133.5 mmol) and the mixture was stirred at ambient temperaturefor 16 hours. The reaction mixture was concentrated in vacuo, theresidue was dissolved in water and extracted with ethyl acetate. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (40% ethylacetate/hexane) to provide propyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a white solid (10 g,96% yield): MS (ES) m/z 239 (M+H).

Step 2: Preparation of propyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of propyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.5 g, 2.09 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate(0.418 g, 2.09 mmol) and triethylamine (0.1 mL, 0.7 mmol) inN-methyl-2-pyrrolidone (10 mL) in sealed tube was heated to 140° C. for5 hours. After cooling to room temperature, the reaction was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo. The crude material waspurified using flash chromatography (50% ethyl acetate/hexane) toprovide propyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow solid (0.2 g, 23% yield): MS (ES) m/z 403 (M+H)

Step 3: Preparation of propyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatehydrochloride Salt

To a solution of propyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 0.49 mmol) in dioxane (5 mL) was added 4M HCl in dioxane (5 mL)at 0° C. and the reaction was allowed to warm to ambient temperature andstir for 5 hours. The solution was concentrated in vacuo and the residuewas washed with diethyl ether to provide propyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HClas an off-white solid (0.15 g, 90% yield): MS (ES) m/z 303 (M+H).

Step 4: Preparation of propyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of propyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HCl(0.15 g, 0.44 mmol) in dichloromethane (10 mL), was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (0.13 g, 0.88 mmol),1-hydroxybenzotriazole (0.12 g, 0.88 mmol), N,N-diisopropylethylamine(0.23 mL, 1.32 mmol), cyanoacetic acid (0.07 g, 0.88 mmol) and themixture stirred at ambient temperature for 16 hours. The reactionmixture was partitioned between dichloromethane and water. The organiclayer was washed with water, brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified using flash chromatography (5%methanol/dichloromethane) to provide propyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.037 g, 23% yield). ¹H NMR (400 MHz, DMSO-d₆ at 80° C.) δ 11.47 (s,1H), 8.74 (s, 1H), 8.56 (s, 1H), 7.16 (s, 1H), 6.66 (s, 1H), 4.18-4.19(m, 3H), 3.94 (m, 2H), 3.73 (m, 1H), 3.52 (m, 1H), 3.27 (m, 2H), 2.08(m, 1H), 1.67-1.88 (m, 5H), 0.97 (t, J=7.6 Hz, 3H); MS (ES) m/z 370(M+H).

Retention time: 10.27 min

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% ammonia in water

Mobile phase (B): ACN

Flow rate: 1.0 mL/min

Synthesis of Example 131: Preparation of 2-methoxyethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of 2-methoxyethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of 2-methoxyethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.45 g, 1.76 mmol),tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.35 g, 1.76 mmol) andtriethylamine (0.1 mL) in N-methyl-2-pyrrolidone (10 mL) was heated to120° C. in a sealed tube for 12 hours. After cooling to ambienttemperature, the reaction mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (70% ethyl acetate/hexane) to provide 2-methoxyethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.5 g, 68% yield): MS (ES) m/z 419 (M+H)

Step 2: Preparation of 2-methoxyethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HClSalt

To a solution of 2-methoxyethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.5 g, 1.19 mmol) in dioxane (5 mL) was added HCl in dioxane (8 mL, 4M)at 0° C. The reaction was allowed to warm to ambient temperature and themixture was stirred for 16 hours. The solution was concentrated invacuo. The residue was washed with diethyl ether to provide2-methoxyethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HClsalt as an off-white solid (0.4 g, 94% yield): MS (ES) m/z 319 (M+H)

Step 3: Preparation of 2-methoxyethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution 2-methoxyethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HClsalt (0.4 g, 1.12 mmol) in dichloromethane (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (0.35 g, 2.26 mmol),1-hydroxybenzotriazole (0.305 g, 2.26 mmol), N,N-diisopropylethylamine(0.58 mL, 3.39 mmol) and cyanoacetic acid (0.19 g, 2.26 mmol) and themixture stirred at ambient temperature for 16 hours. The reactionmixture was partitioned between dichloromethane and water. The organiclayer was washed with water, brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (5%methanol/dichloromethane) to provide 2-methoxyethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.1 g, 23% yield): ¹H NMR (400 MHz, DMSO-d₆ at80° C.) δ 11.49 (s, 1H), 8.66 (br s, 1H), 8.56 (s, 1H), 7.17 (s, 1H),6.66 (s, 1H), 4.35 (t, J=7.6 Hz, 2H), 4.16 (m, 2H), 3.94 (m, 2H), 3.66(t, J=7.6 Hz, 2H), 3.53 (m, 1H), 3.32 (s, 3H), 3.31 (m, 1H), 2.08 (m,1H), 1.66-1.69 (m, 4H); MS (ES) m/z 386 (M+H).

Synthesis of Example 132: Preparation of ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid

To a stirred solution of 3-aminocyclohexane-1-carboxylic acid (5 g,34.91 mmol) in 1,4-dioxane (50 mL) was added 1N sodium hydroxidesolution (2.1 g, 52.4 mmol) and the solution stirred at ambienttemperature for 10 minutes. At this time di-tert-butyldicarbonate (10.4mL, 45.4 mmol) was added and the mixture was stirred at ambienttemperature for 15 hours. The solvent was concentrated in vacuo and theresidue diluted with water and the mixture acidified (pH 4.0) withsaturated potassium bisulfate solution. The aqueous solution wasextracted with dichloromethane. The combined organic layers were washedwith water, brine and dried over anhydrous sodium sulfate. The solutionwas filtered and concentrated in vacuo to provide3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid as anoff-white solid (8 g, 94% yield): MS (ES) m/z 242.1 (M−H).

Step 2: Preparation of tert-butyl (3-(hydroxymethyl)cyclohexyl)carbamate

To a solution of 3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylicacid (6 g, 24.6 mmol) in dry tetrahydrofuran (60 mL) was addedborane-dimethylsulfide (3.51 mL, 36.98 mmol, xM) at −20° C. and theresulting mixture was stirred at ambient temperature for 15 hours. Thereaction was cooled to 0° C. and quenched by adding methanol dropwiseand the mixture was stirred for 30 minutes. The solvent was concentratedin vacuo and the crude material purified by column chromatography(methanol/dichloromethane) to provide tert-butyl(3-(hydroxymethyl)cyclohexyl)carbamate as a colorless oil (4.3 g, 76%yield): MS (ES) m/z 130.2 (M+H).

Step-3: Preparation of tert-butyl (3-formylcyclohexyl)carbamate

To a solution of tert-butyl (3-(hydroxymethyl)cyclohexyl)carbamate (3 g,13.1 mmol) in dry dichloromethane (30 mL) was added Dess-Martinperiodinane (7.21 g, 17.0 mmol) at 0° C. and the mixture stirred atambient temperature for 2 hours. The reaction was cooled to 0° C. andquenched with saturated aqueous sodium bicarbonate solution and a pinchof sodium thiosulphate was added. The mixture was stirred at 0° C. for30 minutes. The emulsion was filtered through celite and washed withdichloromethane. The organic layer was separated, washed with water,brine and dried over anhydrous sodium sulfate. The solution was filteredand concentrated in vacuo to provide tert-butyl(3-formylcyclohexyl)carbamate and carried to next step without furtherpurification (3 g, crude).

Step 4: Preparation of tert-butyl(E)-(3-(2-cyanovinyl)cyclohexyl)carbamate

To a suspension of potassium tert-butoxide (2.32 g, 19.8 mmol) in drytetrahydrofuran (30 mL) was added diethyl (cyanomethyl)phosphonate (3mL, 18.5 mmol) at 0° C. The mixture was stirred for 1 hour and then asolution of tert-butyl (3-formylcyclohexyl)carbamate (3 g, 13.2 mmol) indry tetrahydrofuran (10 mL) was added. The mixture was stirred atambient temperature for 12 hours. The reaction mixture was quenched withwater and extracted with ethyl acetate. The combined organic layers werewashed with water, brine and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo. The crude material waspurified using flash chromatography (1% methanol/dichloromethane) toprovide tert-butyl (E)-(3-(2-cyanovinyl)cyclohexyl)carbamate as acolorless semisolid (1.2 g, 36% yield): MS (ES) m/z 151.2 (M+H).

Step 5: Preparation of tert-butyl (3-(2-cyanoethyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl(E)-(3-(2-cyanovinyl)cyclohexyl)carbamate (1.1 g, 4.39 mmol) in ethylacetate (15 mL) was added palladium on carbon (0.1 g, 50% wet w/w) underan argon atmosphere. The suspension was stirred at ambient temperatureunder a hydrogen atmosphere for 2 hours. The reaction was filteredthrough celite and washed with ethyl acetate. The filtrate wasconcentrated in vacuo to provide tert-butyl(3-(2-cyanoethyl)cyclohexyl)carbamate (1.2 g, crude): MS (ES) m/z 153.2(M+H).

Step 6: Preparation of 3-(3-aminocyclohexyl)propanenitrile

To a solution of tert-butyl (3-(2-cyanoethyl)cyclohexyl)carbamate (1.2g, 4.75 mmol) in dry dichloromethane (20 mL) was added trifluoroaceticacid (1.1 mL, 14.3 mmol) at 0° C. and the mixture was stirred at ambienttemperature for 15 hours. The solvent was concentrated in vacuo, theresidue diluted with ethyl acetate and basified using triethylamine at0° C. The organic layer was washed with water, brine and dried overanhydrous sodium sulfate. The solution was filtered and concentrated invacuo to provide 3-(3-aminocyclohexyl)propanenitrile as a colorless oil(0.6 g, 48% yield): MS (ES) m/z 153.2 (M+H).

Step 7: Preparation of ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a mixture of stereoisomers

To a solution of 3-(3-aminocyclohexyl)propanenitrile (0.25 g, 1.64 mmol)in N-methyl-2-pyrrolidone (10 mL) was added ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.44 g, 1.97 mmol) andtriethylamine (0.7 mL, 4.93 mmol) at room temperature. The mixture wassubjected to microwave irradiation at 170° C. for 1 hour. The reactionmixture was cooled to room temperature, quenched with water andextracted with ethyl acetate. The organic layer was washed with water,brine and dried over sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (ethyl acetate/n-hexane) to provide ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.22 g): MS (ES) m/z 341.2 (M+H).

Ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(Example 132) was subjected to prep.HPLC and two diastereomers wereseparated by the following method.

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% Ammonia in water

Mobile phase (B): ACN

Flow rate: 1.0 mL/min(50:50)

Synthesis of Example 133: (rac)-(cis)-ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 9.08 (d, J=8.4 Hz, 1H), 8.53(s, 1H), 7.15 (t, J=2.8 Hz, 1H), 6.57 (s, 1H), 4.43 (d, J=3.6 Hz, 1H),4.25 (q, J=7.2 Hz, 2H), 2.48 (s, 1H), 1.98 (d, J=8.0 Hz, 1H), 1.60-1.85(m, 5H), 1.42-1.55 (m, 4H), 1.30 (t, J=7.2 Hz, 3H), 1.21 (s, 1H),1.0-1.08 (m, 1H); MS (ES) m/z 341.0 (M+H). Retention time: 4.93 min.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: nHexane:Ethanol with (70:30)

Flow rate: 1.0 ml/min

Synthesis of Example 134: (rac)-(trans)-Ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.52(s, 1H), 7.15 (s, 1H), 6.53 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.93 (d,J=8.0 Hz, 1H), 2.48 (s, 1H), 2.12 (m, 2H), 1.75 (m, 2H), 1.41-1.60 (m,4H), 1.29 (t, J=6.8 Hz, 3H), 1.12-1.21 (m, 2H), 0.88-1.00 (m, 2H); MS(ES) m/z 341.0 (M+H). Retention time: 6.953 min.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: n-Hexane:Ethanol with (70:30)

Flow rate: 1.0 mL/min

Synthesis of Example 135: (cis) ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,enantiomer 1

¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 9.08 (d, J=8.4 Hz, 1H), 8.53(s, 1H), 7.15 (s, 1H), 6.57 (s, 1H), 4.42 (br s, 1H), 4.25 (q, J=6.8 Hz,2H), 2.48 (s, 1H), 1.97-2.00 (m, 1H), 1.83 (m, 1H), 1.60-1.75 (m, 5H),1.42-1.55 (m, 4H), 1.30 (t, J=7.2 Hz, 3H), 1.0-1.08 (m, 1H); MS (ES) m/z341.4 (M+H). Retention time 3.43 min.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: n-hexane:Ethanol with (50:50)

Flow rate: 1.0 mL/min

Synthesis of Example 136: (cis) ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,enantiomer 2

¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 9.08 (d, J=7.6 Hz, 1H), 8.53(s, 1H), 7.15 (s, 1H), 6.57 (s, 1H), 4.42 (br s, 1H), 4.25 (q, J=6.8 Hz,2H), 2.48 (s, 1H), 1.97-2.01 (m, 1H), 1.83 (m, 1H), 1.64-1.70 (m, 5H),1.45-1.55 (m, 4H), 1.30 (t, J=7.2 Hz, 3H), 1.02-1.05 (m, 1H); MS (ES)m/z 341.4 (M+H). Retention time 6.24 min.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: n-hexane:ethanol with (50:50)

Flow rate: 1.0 mL/min

Synthesis of Example 137: (trans) ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateenantiomer 1

¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.52(s, 1H), 7.16 (s, 1H), 6.52 (s, 1H), 4.23 (q, J=6.8 Hz, 2H), 3.92 (br s,1H), 2.12 (m, 2H), 1.98 (t, J=7.6 Hz, 1H), 1.74 (m, 3H), 1.36-1.58 (m,4H), 1.29 (t, J=6.8 Hz, 3H), 1.21 (s, 2H), 0.67-1.00 (m, 1H); MS (ES)m/z 341.4 (M+H). Retention time: 3.489 min.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: n-hexane:ethanol with (50:50)

Flow rate: 1.0 mL/min

Synthesis of Example 138: (trans)-ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,enantiomer 2

¹H NMR (400 MHz, DMSO-d₆): δ 11.63 (s, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.52(s, 1H), 7.15 (s, 1H), 6.60 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.92-4.94(m, 1H), 2.12 (m, 2H), 1.97-2.00 (m, 1H), 1.75 (m, 2H), 1.37-1.60 (m,4H), 1.29 (t, J=6.8 Hz, 3H), 1.21 (s, 2H), 0.68-1.00 (m, 2H); MS (ES)m/z 341.4 (M+H). Retention time: 6.472 min.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: n-hexane:ethanol with (50:50)

Flow rate: 1.0 mL/min

Synthesis of Examples 139 and 140: Preparation of cis and trans(rac)-propyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateExample 139 and 140

Step 1: Preparation of propyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of 3-(3-aminocyclohexyl)propanenitrile (0.3 g, 1.97 mmol)in N-methyl-2-pyrrolidone (13 mL) was added propyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.56 g, 2.36 mmol) andtriethylamine (0.9 mL, 5.91 mmol) at ambient temperature. The mixturewas subjected to microwave irradiation at 170° C. for 1 hour. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith water, brine and dried over anhydrous sodium sulfate. The solutionwas filtered and concentrated in vacuo. The crude material was purifiedusing flash chromatography (10% methanol/dichloromethane) to providepropyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown oil (0.65 g crude): MS (ES) m/z 130.2 (M+H). The cis andtrans isomers were separated using the following chromatographicconditions:

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% ammonia in water

Mobile phase (B): ACN

Flow rate: 1.0 mL/min(50:50)

Synthesis of Example 139: (rac) (cis) propyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 9.08 (d, J=8.0 Hz, 1H), 8.54(s, 1H), 7.15 (s, 1H), 6.57 (s, 1H), 4.42 (br s, 1H), 4.17 (t, J=6.0 Hz,2H), 2.48 (br s, 3H), 1.97-2.17 (m, 1H), 1.61-1.85 (m, 7H), 1.42-1.55(m, 3H), 1.03-1.14 (m, 1H), 0.96 (t, J=7.6 Hz, 3H); MS (ES) m/z 355.1(M+H). Retention time 26.226 min

Synthesis of Example 140: (rac)-(trans)-propyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.53(s, 1H), 7.16 (t, J=2.8 Hz, 1H), 6.53 (s, 1H), 4.15 (t, J=6.8 Hz, 2H),3.92-3.94 (m, 1H), 2.48 (s, 3H), 2.12 (t, J=12.4 Hz, 2H), 1.67-1.79 (m,4H), 1.42-1.56 (m, 4H), 1.07-1.30 (m, 2H), 0.96 (t, J=7.6 Hz, 3H): MS(ES) m/z 355.4 (M+H). Retention time 30.787 min.

Synthesis of Example 141: Preparation of ethyl4-((3-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of tert-butyl (3-hydroxycyclohexyl)carbamate

To a solution tert-butyl (3-oxocyclohexyl)carbamate (1 g, 4.69 mmol) inmethanol (20 mL) was added sodium borohydride (0.26 g, 7.04 mmol) andthe mixture was stirred at ambient temperature for 1 hour. The reactionwas quenched with water and methanol was removed in vacuo. The residuewas extracted with ethyl acetate. The organic layer was washed withwater, brine and dried over sodium sulfate and concentrated in vacuo toprovide tert-butyl (3-hydroxycyclohexyl)carbamate as a colorless liquid(1 g, 100% yield): MS (ES) m/z 160.1 (M-56).

Step 2: Preparation of 3-aminocyclohexan-1-ol, HCl Salt

To a solution of tert-butyl (3-hydroxycyclohexyl)carbamate (1 g, 4.65mmol) in dichloromethane (20 mL) and was added dioxane.HCl (1M, 20 mL)and the mixture stirred at ambient temperature for 12 hours. The mixturewas concentrated in vacuo to provide 3-aminocyclohexan-1-ol HCl salt(0.65 g, crude): MS (ES) m/z 116 (M+H)

Step-3: Preparation of ethyl4-((3-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.96 g, 4.30 mmol) inN-methyl-2-pyrrolidone (2 mL) was added 3-aminocyclohexan-1-ol HCl salt(0.65 g, 4.30 mmol) and triethylamine (0.3 mL). The solution was heatedin a sealed tube at 170° C. for 16 hours. After cooling to ambienttemperature, the reaction was quenched with water and extracted withdichloromethane. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified by chiral HPLCpurification to provide ethyl4-((3-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid as a mixture of stereoisomers. (0.01 g): ¹H NMR(400 MHz, DMSO-d₆) δ 11.62 (br s, 1H), 8.77 (d, J=8.0 Hz, 1H), 8.51 (s,1H), 7.16 (s, 1H), 6.51 (s, 1H) 4.65 (d, J=4.4 Hz, 1H), 4.21-4.26 (m,2H), 3.92-3.99 (m, 1H), 3.56-3.62 (m, 1H) 2.25 (m, 1H), 1.98 (m, 1H),1.82 (m, 1H), 1.69-1.73 (m, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.12-1.20 (m,4H); MS (ES) m/z 304.2 (M+H).

Retention time: 6.959 min.

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

mobile phase: MTBE:IPA with 0.1% DEA (90:10)

Flow rate: 1.0 mL/minute

Synthesis of Example 142: Preparation of ethyl4-((3-(cyanomethyl)-4-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of 1-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolidine

To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.1mmol) in cyclohexane (200 mL) was added pyrrolidine (5.8 mL, 70.25 mmol)and p-toluenesulfonic acid (0.24 g, 1.28 mmol). The solution was heatedto reflux in a Dean-Stark apparatus for 3 hours. After cooling thesolution to ambient temperature, the reaction was concentrated in vacuoto remove cyclohexane and traces of pyrrolidine. The crude product wasused for the next step without further purification (13.4 g).

Step 2: Preparation of2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetonitrile

A stirred solution of 1-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolidine(13.4 g, 64.11 mmol) and 2-chloroacetonitrile (4.8 mL, 76.48) in1,4-dioxane (250 mL) was heated to reflux for 5 hours. The reactionmixture was cooled to ambient temperature and concentrated in vacuo. Thecrude material was purified by using flash chromatography (30% ethylacetate/hexane) to provide2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetonitrile as a yellow oil(4.72 g, 37% yield): MS (ES) m/z 196.1 (M+H).

Step 3: Preparation of2-(8-hydroxy-1,4-dioxaspiro[4.5]decan-7-yl)acetonitrile

To a stirred solution of2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetonitrile (4.7 g, 24.1 mmol)in methanol (50 mL) was added sodium borohydride (91.37 g, 36.5 mmol) inportions at 0° C., and the solution was stirred at ambient temperaturefor 2 hours. The reaction mixture was concentrated in vacuo and theresidue was dissolved in ethyl acetate, washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo to provide2-(8-hydroxy-1,4-dioxaspiro[4.5]decan-7-yl)acetonitrile as a colourlessoil (4.57 g, 76% yield): MS (ES) m/z 198.1 (M+H).

Step 4: Preparation of 2-(2-hydroxy-5-oxocyclohexyl)acetonitrile

A solution of hydroxy-1,4-dioxaspiro[4.5]decan-7-yl)acetonitrile (3.5 g,17.94 mmol) and p-toluenesulfonic acid monohydrate (1.0 g, 5.38 mmol) inacetone:water (30:10 mL) was heated to 100° C. for 2 hours. Aftercooling to ambient temperature, the reaction mixture was concentrated invacuo and the residue was dissolved in ethyl acetate which was washedwith water, brine and dried over anhydrous sodium sulfate. The solutionwas filtered and concentrated in vacuo to provide2-(2-hydroxy-5-oxocyclohexyl)acetonitrile as a brown coloured oil (2.25g, 83% yield): MS (ES) m/z 154.1 (M+H).

Step 5: Preparation of 2-(5-amino-2-hydroxycyclohexyl)acetonitrile

To a stirred solution of 2-(2-hydroxy-5-oxocyclohexyl)acetonitrile (2.24g, 14.64 mmol) in methanol (50 mL) was added ammonium acetate (2.25 g,29.28 mmol) and sodium borohydride (1.38 g, 21.96 mmol) and the mixturewas stirred at ambient temperature for 15 hours. The reaction mixturewas concentrated in vacuo to provide2-(5-amino-2-hydroxycyclohexyl)acetonitrile as a colourless gummy solid(10 g, crude): MS (ES) m/z 155.1 (M+H).

Step 6: Preparation of ethyl4-((3-(cyanomethyl)-4-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

A solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(2.0 g, 8.93 mmol), 2-(5-amino-2-hydroxycyclohexyl)acetonitrile (2.0 g,13.4 mmol), and a catalytic amount of triethylamine inN-methylpyrrolidine (40 mL) was subjected to microwave irradiation at180° C. for 2 hours. After cooling the reaction mixture was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine, dried over anhydrous sodium sulphate, filteredand concentrated in vacuo. The crude material was purified using flashchromatography (5% methanol/dichloromethane) to provide ethyl4-((3-(cyanomethyl)-4-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.06 g, 2% yield): ¹HNMR (400 MHz, DMSO-d₆, at90° C.) δ 11.61 (br s, 1H), 8.93 (d, J=8 Hz, 1H), 8.52 (s, 1H), 7.14 (s,1H), 6.55 (s, 1H), 4.50 (br s, 1H), 4.25 (q, J=6.8 Hz, 2H), 4.09 (br s,1H), 3.65 (br s, 1H), 2.1-2.2 (m, 2H), 1.64-1.74 (m, 3H), 1.51-1.59 (m,3H), 1.27-1.31 (m, 4H); MS (ES) m/z 304.1 (M+H).

Synthesis of Example 143: Preparation of ethyl(S)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of ethyl(S)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (7 g, 31.2 mmol) inN-methyl-2-pyrrolidone (40 mL) was added tert-butyl(S)-3-aminopiperidine-1-carboxylate (12.5 g, 62.5 mmol) andtriethylamine (0.4 mL) in a sealed tube. The mixture was heated to 170°C. for 5 hours. After cooling to ambient temperature, the reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (50% ethylacetate/hexane) to provide ethyl(S)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a colourless oil (7 g, 57% yield): MS (ES) m/z 389.2 (M+H).

Step 2: Preparation of ethyl(S)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatehydrochloride

To a stirred solution of ethyl(S)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(7 g, 18.0 mmol) in 1,4-dioxane (10 mL) was added (4M) hydrochloride in1,4-dioxane (15 mL) and the mixture was stirred under a nitrogenatmosphere at ambient temperature for 12 hours. The reaction mixture wasconcentrated in vacuo to provide ethyl(S)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatehydrochloride as an off-white solid (4 g, crude): MS (ES) m/z 289.3(M+H).

Step 3—Preparation of ethyl(S)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl(S)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatehydrochloride (2.5 g, 8.68 mmol) in N,N-dimethylformamide (25 mL) wereadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.6g, 17.3 mmol), 1-hydroxybenzotriazole (2.3 g, 17.3 mmol),N,N-diisopropylethylamine (2.2 g, 17.3 mmol) and cyanoacetic acid (1.4g, 17.3 mmol). The mixture was then stirred at ambient temperature for18 hours. The reaction mixture was quenched with water and extractedwith dichloromethane. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide ethyl(S)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow solid (1.2 g, 40% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.7(br s, 1H), 8.86-8.80 (m, 1H), 8.54 (s, 1H), 7.20 (s, 1H), 6.67 (s, 1H),4.06-4.27 (m, 3H), 3.63-4.00 (m, 4H), 3.40-3.45 (m, 1H), 3.10-3.15 (m,1H), 2.05 (br s, 1H), 1.64-1.71 (m, 3H), 1.28-1.31 (t, J=12 Hz, 3H); MS(ES) m/z 356.2 (M+H).

Synthesis of Example 144: Preparation of ethyl(R)-4-((1-(2-cyano-2-methylpropanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1g, 8.68 mmol) in dichloromethane (5 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.HCl (0.1 g, 0.69 mmol),1-hydroxybenzotriazole (0.09 g, 0.69 mmol), N,N-diisopropylethylamine(0.09 g, 0.69 mmol) and cyanoacetic acid (0.08 g, 0.69 mmol). Themixture was stirred at ambient temperature for 18 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (5%methanol/dichloromethane) to provide ethyl(R)-4-((1-(2-cyano-2-methyl-propanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow solid (0.015 g, 40% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.67 (br s, 1H), 8.89-8.91 (m, 1H), 8.53 (s, 1H), 7.19 (s, 1H), 6.66(s, 1H), 4.21-4.27 (m, 3H), 3.9-3.95 (m, 1H), 3.71 (m, 3H), 2.1-2.2 (brs, 1H), 1.85-1.6 (m, 3H), 1.50-1.54 (m, 6H), 1.28-1.31 (t, J=12 Hz, 3H);MS (ES) m/z 384.1 (M+H).

Synthesis of Example 145: Preparation of cyclopropylmethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.12 g, 0.33 mmol) in cyclopropylmethanol (5 mL) was added cesiumcarbonate (0.53 g, 1.65 mmol). The mixture was stirred at ambienttemperature for 12 hours. The reaction mixture was concentrated in vacuoand the crude material was purified by flash chromatography (4%methanol/dichloromethane) to provide cyclopropylmethyl(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (0.013 g, 10% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.70(br s, 1H), 8.77-8.84 (m, 1H), 8.56 (s, 1H), 7.20 (s, 1H), 6.67 (s, 1H),4.16-4.29 (m, 2H), 4.05-4.06 (m, 3H), 3.77-3.99 (m, 2H), 3.62-3.70 (m,1H), 3.44 (m, 1H), 3.13-3.15 (m, 1H), 2.05 (m, 1H), 1.64 (m, 3H),1.21-1.29 (m, 2H), 0.53-0.55 (m, 1H), 0.32-0.33 (m, 1H); MS (ES) m/z382.1 (M+H).

Synthesis of Example 146: Preparation of ethyl4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of ethyl4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.35 g, 1.56 mmol) in N-methyl-2-pyrrolidone (5 mL) was added benzyl(2S,5R)-5-amino-2-methylpiperidine-1-carboxylate (0.65 g, 2.65 mmol) andtriethylamine (0.5 mL). The mixture was heated to 180° C. undermicrowave irradiation for 1 hour. The reaction mixture was cooled toambient temperature, quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine and dried overanhydrous sodium sulfate. The reaction mixture was filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (40% ethyl acetate/hexane) to provide ethyl4-(((3R,6S)-1-((benzyloxy)-carbonyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow solid (0.3 g, 44% yield).

Step 2: Preparation of ethyl 4-(((3R, 6S)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.3 g, 0.68 mmol) in tetrahydrofuran (5 mL) was added palladium oncarbon (0.3 g, 50% wet w/w). The reaction mixture was placed under ahydrogen atmosphere and stirred at room temperature for 12 hours. Thereaction mixture was filtered through celite and washed with 50%methanol/ethyl acetate (100 mL). The filtrate was concentrated in vacuoto provide ethyl 4-(((3R, 6S)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid(0.2 g, crude): MS (ES) m/z 303.2 (M+H).

Step 3: Preparation of ethyl4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 0.66 mmol) in N,N-dimethylformamide (2 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.11 g,1.32 mmol), 1-hydroxybenzotriazole (0.17 g, 1.32 mmol),N,N-diisopropylethylamine (0.18 g, 1.32 mmol) and cyanoacetic acid (0.11g, 1.32 mmol) and the mixture stirred at ambient temperature for 18hours. The reaction mixture was quenched with water and extracted withdichloromethane. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide ethyl(R)-4-((1-(2-cyano-2-methylpropanoyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a brown solid (0.07 g, 28% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.718(br s, 1H), 8.75 (m, 1H), 8.54 (s, 1H), 7.20 (s, 1H), 6.63-6.66 (m, 1H),4.67 (m, 1H), 3.84-4.28 (m, 6H), 1.62-1.97 (m, 5H), 1.11-1.32 (m, 6H);MS (ES) m/z 370.2 (M+H).

Synthesis of Example 147: Preparation of4-(((1S,3R)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a stirred solution of propyl4-(((1S,3R)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.04 g, 0.112 mmol) in n-propanol (6 mL) was added lithium hydroxidemonohydrate (0.04 g, 1.12 mmol) at 0° C. and the mixture was heated at50° C. for 32 hours. After cooling the reaction mixture was concentratedin vacuo and the residue was dissolved in water which was washed withdiethyl ether. The aqueous layer was acidified to pH 2.0 with saturatedpotassium bisulphate solution at 0° C. and then extracted with 5%methanol/dichloromethane. The organic layer was dried over anhydroussodium sulphate, filtered and concentrated in vacuo. The obtained crudeproduct was triturated with n-pentane to provide 4-(((1S,3R)-3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as an off-white solid (0.02 g, 50% yield): ¹H NMR (400 MHz,DMSO-d₆): δ 12.20 (br s, 1H), 11.52 (s, 1H), 9.15 (br s, 1H), 8.49 (s,1H), 7.12 (s, 1H), 6.50 (s, 1H), 3.91 (d, J=8.0 Hz, 1H), 2.52 (s, 1H),2.11 (t, J=12.0 Hz, 2H), 1.74 (t, J=16.0 Hz, 2H), 1.41-1.57 (m, 4H),1.11-1.21 (m, 2H), 0.79-0.98 (m, 2H); MS (ES) m/z 313.0 (M+H).

Synthesis of Examples 148-150. Preparation and separation ofstereoisomers of 2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Preparation of 2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of 3-(3-aminocyclohexyl)propanenitrile (0.27 g,1.77 mmol) in N-methyl-2-pyrrolidone (15 mL) was added 2-methoxyethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.54 g, 2.128 mmol)and triethylamine (0.74 mL, 5.31 mmol). The mixture was then subjectedto a microwave irradiation at 170° C. for 1 hour. After cooling toambient temperature, the reaction mixture was diluted with ethyl acetateand washed with water, brine, dried over sodium sulphate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (50% ethyl acetate/hexane) to provide crude racemic2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatean off-white solid (0.42 g, crude). Racemic 2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.42 g) was purified by prep HPLC using the following method to give0.115 g of pure racemic compound as an off white solid.

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% ammonia in water

Mobile phase (B): ACN

Flow rate: 1.0 mL/min

T/% B: 0/20, 10/70, 25/90, 27/20, 30/20

RT=12.927 min

The stereoisomers of 2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatewere separated using the following chromatographic conditions.

Column: CHIRALPAK IA (100 mm×4.6 mm×3 mic)

Mobile phase: n-hexane:ethanol with 0.1% DEA (90:10)

Flow rate: 1.0 mL/min

Synthesis of Example 148: Isolation of racemic, trans-2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Isolated as an off-white solid (0.02 g, 17% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 11.66 (s, 1H), 9.03 (d, J=8.0 Hz, 1H), 8.53 (s, 1H), 7.15 (s,1H), 6.57 (d, J=2.8 Hz, 1H), 4.42 (t, J=4.0 Hz, 1H), 4.32 (t, J=4.4 Hz,2H), 3.64 (t, J=4.8 Hz, 2H), 3.29 (d, J=5.6 Hz, 3H), 2.44 (s, 2H),1.81-1.84 (m, 1H), 1.70-1.74 (m, 3H), 1.60-1.67 (m, 2H); 1.41-1.55 (m,4H); 1.00-1.08 (m, 1H); MS (ES) m/z 371.1 (M+H). Retention time 8.652min.

Synthesis of Example 149: Isolation of one enantiomer ofcis-2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,enantiomer 1

Isolated as an off-white solid (0.03 g, 29% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 11.67 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.52 (s, 1H), 7.16 (s,1H), 6.57 (s, 1H), 4.31 (t, J=4.4 Hz, 2H), 3.94 (t, J=3.6 Hz, 1H), 3.63(t, J=4.4 Hz, 2H), 3.29 (d, J=4.8 Hz, 3H), 2.50-2.52 (m, 2H), 2.12 (t,J=12.0 Hz, 2H), 1.74 (t, J=16.0 Hz, 2H), 1.41-1.51 (m, 3H); 1.05-1.31(m, 2H), 0.83-1.00 (m, 2H); MS (ES) m/z 371.1 (M+H). Retention time10.04 min.

Synthesis of Example 150: Isolation of the opposite enantiomer of cis2-methoxyethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,enantiomer 2

Isolated as an off-white solid (0.03 g, 28% yield); ¹H NMR (400 MHz,DMSO-d₆) δ 11.67 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.52 (s, 1H), 7.16 (d,J=2.8 Hz 1H), 6.53 (d, J=3.2 Hz, 1H), 4.31-4.46 (m, 2H), 3.90-3.97 (m,1H), 3.66 (d, J=20.0 Hz, 2H), 3.29 (s, 3H), 2.50 (s, 2H), 2.12 (t,J=12.0 Hz, 2H), 1.74 (t, J=15.6 Hz, 2H), 1.41-1.60 (m, 3H), 1.08-1.31(m, 2H), 0.68-1.0 (m, 2H); MS (ES) m/z 371.1 (M+H). Retention time 13.39min.

Synthesis of Example 151-152: Preparation of cis- and trans-racemicmethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of 3-(3-aminocyclohexyl)propanenitrile (0.07 g,0.459 mmol) in N-methyl-2-pyrrolidone (3 mL) was added ethyl4-chloro-1H-pyrrolo[2,3-]pyridine-5-carboxylate (0.123 g, 0.551 mmol)and triethylamine (0.2 mL, 1.337 mmol). The mixture was subjected to amicrowave irradiation at 170° C. for 1 hour. After cooling to ambienttemperature, the reaction mixture was diluted with ethyl acetate andwashed with water, brine, dried over anhydrous sodium sulphate, filteredand concentrated in vacuo. The crude material was purified by flashchromatography (50% ethyl acetate/hexane) to provide ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow semisolid (0.38 g, 36% yield): MS (ES) m/z 341.1 (M+H).

Step 2: Preparation of methyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 0.587 mmol) in dry methanol (8 mL) was added cesium carbonate(0.957 g, 2.937 mmol) at 0° C. and the resulting mixture was stirred atroom temperature for 72 hours. The reaction mixture was concentrated invacuo. The residue was diluted with water and extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo. The crude product waspurified by column chromatography (50% ethyl acetate/hexane) to providemethyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a colourless oil (0.08 g, 42% yield): MS (ES) m/z 327.1 (M+H).

The cis- and trans-diastereomers of methyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatewere separated using the following chromatographic conditions:

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase (A): 0.1% ammonia in water

Mobile phase (B): ACN

Flow rate: 1.0 mL/min (50:50)

Synthesis of Example 151: trans-racemic-methyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Isolated as an off-white solid (0.01 g, 13% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 11.61 (s, 1H), 9.07 (d, J=8.4 Hz, 1H), 8.51 (s, 1H), 7.15 (t,J=2.8 Hz, 1H), 6.57 (d, J=1.2 Hz, 1H), 4.43 (t, J=3.6 Hz, 1H), 3.78 (s,3H), 2.47 (s, 2H), 1.82-1.85 (m, 1H), 1.61-1.75 (m, 5H), 1.41-1.55 (m,4H), 1.0-1.08 (m, 1H); MS (ES) m/z 327.2 (M+H). Retention time 12.729min.

Synthesis of Example 152: cis-racemic-methyl4-((3-(2-cyanoethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Isolated as an off-white solid (0.04 g, 50% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 11.63 (s, 1H), 8.72 (d, J=8.0 Hz, 1H), 8.50 (s, 1H), 7.15 (d,J=2.0 Hz, 1H), 6.53 (d, J 1.2 Hz, 1H), 3.90-3.98 (m, 1H), 3.77 (s, 3H),2.50 (s, 2H), 2.12 (t, J=12.8 Hz, 2H), 1.75 (t, d, J=16.4 Hz, 2H),1.41-1.60 (m, 4H), 1.13-1.21 (m, 1H), 0.85-1.0 (m, 2H); MS (ES) m/z327.1 (M+H). Retention time: 14.252 min.

Synthesis of Examples 153-155: Preparation of stereoisomers ethyl4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of tert-butyl(3-(hydroxymethyl)cyclopentyl)carbamate

To a stirred solution of3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (2 g, 8.73mmol) in dry tetrahydrofuran (30 mL) was added borane-dimethylsulfide(1.07 mL, 11.35 mmol) at 0° C. and the mixture was stirred at ambienttemperature for 15 hours. The reaction mixture was cooled to 0° C.,quenched with methanol and then stirred for 30 minutes. The reactionmixture was concentrated to provide tert-butyl(3-(hydroxymethyl)cyclopentyl)carbamate as a colourless liquid (2.5 g,crude): MS (ES) m/z 160.2 (M−56).

Step 2: Preparation of tert-butyl (3-formylcyclopentyl)carbamate

To a stirred solution of tert-butyl(3-(hydroxymethyl)cyclopentyl)carbamate (1 g, 4.65 mmol) in drydichloromethane (30 mL) was added Dess-Martin periodinane (2.95 g, 6.97mmol) at 0° C. The mixture was warmed to ambient temperature and stirredfor 2 hours. The reaction mixture was cooled to 0° C. and quenched withsaturated sodium bicarbonate. The organic layer was separated, washedwith brine, dried over anhydrous sodium sulphate, filtered andconcentrated in vacuo to provide tert-butyl(3-formylcyclopentyl)carbamate as a colourless liquid (1.1 g, crude).

Step 3: Preparation of tert-butyl(E)-(3-(2-cyanovinyl)cyclopentyl)carbamate

To a suspension of potassium tert-butoxide (0.86 g, 5.16 mmol) in drytetrahydrofuran (30 mL) was added diethyl (cyanomethyl)phosphonate (1.16mL, 7.23 mmol) at 0° C. and the mixture stirred for 1 hour. A solutionof tert-butyl (3-formylcyclopentyl)carbamate (1.1 g crude, 5.16 mmol) indry tetrahydrofuran (10 mL) was then added. The resulting mixture wasstirred at ambient temperature for 12 hours. The reaction mixture wasdiluted with ethyl acetate and washed with water and brine. The organiclayer was dried over anhydrous sodium sulphate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (20% ethyl acetate/hexane) provide tert-butyl(E)-(3-(2-cyanovinyl)cyclopentyl)carbamate as a colourless liquid (0.25g, 21% yield): MS (ES) m/z 181.2 (M−56).

Step 4: Preparation of tert-butyl (3-(2-cyanoethyl)cyclopentyl)carbamate

To a solution of tert-butyl (E)-(3-(2-cyanovinyl)cyclopentyl)carbamate(0.25 g, 1.05 mmol) in ethyl acetate (15 mL) was added palladium oncarbon (0.2 g, 50% wet w/w) at room temperature under an argonatmosphere. The suspension was stirred at ambient temperature under ahydrogen atmosphere for 12 hours. The reaction mixture was filteredthrough celite, washed with ethyl acetate and the filtrate wasconcentrated in vacuo. The crude material was purified by flashchromatography (20% ethyl acetate/hexane) to provide tert-butyl(3-(2-cyanoethyl)cyclopentyl)carbamate as a colourless liquid (0.12 g,48% yield): MS (ES) m/z 183.1 (M−56).

Step 5: Preparation of3-(3-aminocyclopentyll)propanenitrile.trifluoroactic acid

To a solution of tert-butyl (3-(2-cyanoethyl)cyclopentyl)carbamate (0.12g, 0.54 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid(0.5 mL) at 0° C. and the solution was stirred at ambient temperaturefor 3 hours. The reaction mixture was concentrated in vacuo to provide3-(3-aminocyclopentyll)propanenitrile trifluoroactic acid as acolourless semi solid (0.1 g, crude): MS (ES) m/z 139.2 (M+H).

Step 6: Preparation of ethyl4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of 3-(3-aminocyclopentyll)propanenitriletrifluoroactic acid (0.1 g, 0.42 mmol) in N-methyl-2-pyrrolidone (1 mL)was added ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.09g, 0.42 mmol) and triethylamine (0.1 mL). The reaction mixture was thenheated to 170° C. for 16 hours. The reaction mixture was diluted withethyl acetate, washed with water and brine. The organic layer was driedover anhydrous sodium sulphate, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (6%methanol/dichloromethane) to give ethyl4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off white solid (0.08 g, 57% yield): MS (ES) m/z 327.1 (M+H).

Two of the stereoisomers of this compound could be isolated by chiralchromatography and the other 2 were isolated as a mixture using thefollowing conditions.

Analytical Conditions:

Column: CHIRALPAK IC (100 mm×4.6 mm×3 mic)

Mobile phase: n-hexane:ethanol with 0.1% DEA (80:20)

Flow rate: 1.0 mL/min

Synthesis of Example 153: Ethyl4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a mixture of 2 stereoisomers

Isolated as an off-white solid (0.022 g, 27% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 11.63 (s, 1H), 8.81 (d, J=6.8 Hz, 1H), 8.51 (s, 1H), 7.15 (s,1H), 6.65 (s, 1H), 4.54-4.48 (m, 1H), 4.23 (q, J=6.8 Hz, 2H), 2.48-2.30(m, 1H), 2.22-2.08 (m, 2H), 1.92-1.81 (m, 2H), 1.66-1.31 (m, 4H), 1.29(t, J=7.2 Hz, 3H), 1.23-1.17 (m, 2H); MS (ES) m/z 327.1 (M+H). Mixtureof 2 stereoisomers with retention times 6.96 and 7.68 min.

Synthesis of Example 154: Ethyl4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,single stereoisomer 1

Isolated as an off-white solid (0.0056, 7% yield): ¹H NMR (400 MHz,DMSO-d₆): δ 11.63 (br s, 1H), 8.82 (d, J=6.8 Hz, 1H), 8.51 (s, 1H), 7.15(s, 1H), 6.65 (s, 1H), 4.49-4.47 (m, 1H), 4.23 (q, J=6.8 Hz, 2H),2.41-2.37 (m, 1H), 2.17-2.03 (m, 3H), 1.95-1.89 (m, 2H), 1.67-1.62 (m,3H), 1.29 (t, J=6.8 Hz, 3H), 1.27-1.12 (m, 2H); MS (ES) m/z 327.1 (M+H).Retention time 12.16 min.

Synthesis of Example 155: Ethyl4-((3-(2-cyanoethyl)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate,single stereoisomer 2

Isolated as an off-white solid (0.0138 g, 17% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 11.63 (s, 1H), 8.81 (d, J=6.4 Hz, 1H), 8.51 (s, 1H), 7.15 (s,1H), 6.64 (s, 1H), 4.54 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.22-2.09(m, 3H), 1.94-14.81 (m, 3H), 1.64-1.55 (m, 3H), 1.31 (t, J=6.8 Hz, 3H),1.27-1.21 (m, 2H); MS (ES) m/z 327.1 (M+H). Retention time 14.02.

Synthesis of Example 156: Preparation of ethyl4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Step 1: Preparation of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.5 g, 1.18 mmol) in tetrahydrofuran (10 mL) was added Pd/C (0.05 g,50% w/w wet) under argon atmosphere and the resulting mixture wasstirred at ambient temperature under hydrogen atmosphere (balloonpressure) for 18 hours. The reaction mixture was filtered through celiteand washed with methanol. The filtrate was concentrated in vacuo and thecrude was triturated with diethyl ether to provide ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as apale brown solid (0.21 g, 61% yield): MS (ES) m/z 289.2 (M+H).

Step 2: Preparation of ethyl4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1g, 0.35 mmol) in dry N,N-dimethyl formamide (7 mL) was added(S)-2,2-difluorocyclopropane-1-carboxylic acid (0.06 g, 0.52 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.13 g,0.69 mmol), hydroxybenzotriazole (0.09 g, 0.69 mmol) andN,N-diisopropylethylamine (0.18 mL, 1.038 mmol) at 0° C. The reactionmixture was stirred at ambient temperature for 18 hours. The reactionmixture was quenched with ice water and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The crude material was purifiedusing flash chromatography (60% ethyl acetate/hexane) to provide ethyl4-(((R)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.04 g, 29% yield): ¹H NMR (400 MHz, DMSO-d₆, at60°): δ 11.54 (s, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 7.16 (s, 1H), 6.65(s, 1H), 4.25 (s, 3H), 3.70-4.12 (m, 2H), 3.49 (s, 2H), 2.10 (s, 1H),1.57-1.82 (m, 6H), 1.30 (s, 3H). MS (ES) m/z 393.1 (M+H)

Synthesis of Example 157: Preparation ofethyl-4-(((R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl(R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1g, 0.35 mmol) in dry N,N-dimethyl formamide (7 mL) was added(S)-2,2-difluorocyclopropane-1-carboxylic acid (0.06 g, 0.52 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.13 g,0.69 mmol), hydroxybenzotriazole (0.09 g, 0.69 mmol) andN,N-diisopropylethylamine (0.18 mL, 1.038 mmol) at 0° C. The reactionmixture was stirred at ambient temperature for 18 hours. The reactionmixture was quenched with ice water and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The crude material was purifiedusing flash chromatography (60% ethyl acetate/hexane) to provideethyl-4-(((R)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas an off-white solid (0.05 g, 40% yield): ¹HNMR at 70° C. (400 MHz,DMSO-d₆ at 70°): δ 11.49 (s, 1H), 8.78 (s, 1H), 8.55 (s, 1H), 7.14 (s,1H), 6.61 (s, 1H), 4.26-4.27 (m, 3H), 3.79-3.93 (m, 2H), 3.40-3.54 (m,2H), 2.11 (brs, 1H), 1.73-1.96 (m, 6H), 1.31 (s, 3H); MS (ES) m/z 393.1(M+H).

Biological Activity Assay

JAK1 and JAK3 Enzyme Activity Assays

The activity of JAK3 (a.a. 781-1124, ThermoFisher) was quantified bymeasuring the phosphorylation of SRCtide (FAM-GEEPLYWSFPAKKK-NH₂).Kinase reactions were run in a 384-well Greiner plate with 2% final DMSOconcentration under the buffer conditions of 20 mM HEPES, pH 7.5, 10 mMMgCl₂, 0.01% BSA, and 0.0005% Tween-20. The kinase reaction componentswere 2.5 nM JAK3, 1 μM SRCtide peptide and 1 uM ATP. Examples weretested in dose-response starting at 2 μM (11 concentrations, 3-foldserial dilution, duplicate reactions). The reactions were incubated atroom temperature for 40 minutes, then stopped by adding a 1:1 volume of30 mM EDTA in 20 mM HEPES, pH 7.5 (15 mM EDTA final). After the reactionwas stopped, the phosphorylated and unphosphorylated peptides wereseparated and quantified using a Caliper LC3000/EZ-Reader system and HTSWell Analyzer Software (Caliper, A PerkinElmer Company, Hopkinton,Mass.). GraFit (Erithacus Software Ltd., Horley, U.K.) was used tocalculate inhibitor potency by fitting dose-response data to the4-parameter logistical IC₅₀ equation.

The inhibitory potency of candidate compounds of JAK1 done at ThermoFisher Scientific in their Selectscreen using a Z-lyte assay. The2×JAK1/Tyr 06 mixture is prepared in 50 mM HEPES pH 6.5, 0.01% BRIJ-35,10 mM MgCl2, 1 mM EGTA, 0.02% NaN₃. The final 10 μL of the KinaseReaction consists of 21.2-91.5 ng JAK1 and 2 μM Tyr 06 in 50 mM HEPES pH7.0, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA, 0.01% NaN₃. After the 1 hourKinase Reaction incubation, 5 μL of a 1:128 dilution of DevelopmentReagent is added.

Background signal is defined in the absence of enzyme and uninhibitedsignal is defined in the presence of vehicle (2% DMSO) alone. Compoundswere evaluated in an 11 point dose-response ranging from 20 mM to 0.34nM. IC₅₀ values of compounds are determined using a 4 parameterlogistical fit of emission ratio as a function of the concentration ofcompound. The results are shown in Table 2.

TABLE 2 JAK1 Inhibition IC₅₀ JAK3 Inhibition IC₅₀ +++ indicates ≤ 0.01μM +++ indicates ≤ 0.01 μM ++ indicates 0.01-0.1 μM ++ indicates0.01-0.1 μM Example + indicates 0.1-1 μM + indicates 0.1-1 μM No −indicates > 1 μM − indicates > 1 μM   1 ++ ++   3 +++ +++  21 ++ +++  24+++ +++  34 + +  68A + +  68B + ++  69 + +  70 ++ +  72 ++ ++  73 +++ ++ 74 ++ ++  75 ++ ++  92 +++ +++  94 Not Determined ++ 113 ++ ++ 117 ++++++ 118 +++ ++ 119 + + 120 + + 121 + + 123 +++ +++ 123 +++ +++ 124 ++ ++125 +++ +++ 126 ++ ++ 127 +++ ++ 128 ++ +++ 129 +++ +++ 130 +++ +++ 131++ ++ 132 +++ +++ 133 +++ +++ 134 +++ +++ 135 +++ +++ 136 ++ ++ 137 ++++++ 138 ++ +++ 139 +++ +++ 140 +++ +++ 141 ++ ++ 142 +++ ++ 143 + ++ 144++ ++ 145 +++ ++ 146 +++ +++ 147 + + 148 ++ +++ 149 + ++ 150 +++ +++ 151+++ +++ 152 +++ +++ 153 +++ +++ 154 + ++ 155 + ++ 156 Not Determined ++JAK Cellular Target Modulation Assays

Target modulation was based upon the ability of a compound to inhibitJAK isoform specific phosphorylation of selected substrates. IL-2stimulated STAT5 phosphorylation on Tyr694 was used to assess JAK1/3compound selectivity. GM-CSF stimulated STAT5 phosphorylation on Tyr694was used to assess JAK2 compound selectivity. IFNγ stimulated STAT1phosphorylation on Tyr701 was used to assess JAK1/2 compoundselectivity. For all three assays, human PBMC from frozen stocks werethawed, pelleted, resuspended in complete media (90% RPMI, 10% heatinactivated FBS, 10 mM HEPES, 47 μM 2-ME, pen/strep) and placed in wellsof a 96 well V-bottom plate at 200,000 per well in 120 μl completemedia. Compounds were added as 15 μl per well of 10× working stocksolutions in complete media with 1% DMSO (or medium with 1% DMSO forcontrols) and placed on a plate shaker in a 37° C. incubator with 5% CO₂for 1 hour with gentle shaking (setting of 3). Stimulation used theaddition of soluble cytokines. For the JAK1/3 phospho-STAT5 assay, 15 μlof 10× working stock recombinant human IL-2 was added to a finalconcentration of 25 ng/ml. For the JAK2 phospho-STAT5 assay, 15 μl of10× working stock recombinant human GM-CSF was added to a finalconcentration of 5 ng/ml. For the JAK1/2 phospho-STAT1 assay, 15 μl of10× working stock of recombinant human IFNγ was added to a finalconcentration of 10 ng/ml. Plates were then placed back on the plateshaker in the incubator for an additional 5, 5 and 10 minutesrespectively upon which the plates were removed from the incubator,sealed with a plate sealer and the cells pelleted at 400×g for 5minutes. After pelleting, the media was removed by aspiration and thecells were lysed in ELISA specific cell lysis buffer. The levels ofphospho-STAT5 were determined using a Phospho (Tyr694)/Total STAT5a,bWhole Cell Lysate kit from Meso Scale Discovery. Levels of phospho-STAT1were determined using a CST-PathScan Phospho-STAT1 (Tyr701) SandwichELISA kit. The results are shown in Table 3.

TABLE 3 IL2-STAT5 Inhibition IC₅₀ Infγ-STAT1 IC₅₀ ++ indicates ≤ 0.1 μM++ indicates ≤ 0.1 μM Example + indicates 0.1-1 μM + indicates 0.1-1 μMNo − indicates > 1 μM − indicates > 1 μM  1 + −  3 ++ +  21 + −  24 ++ + 34 + −  68A − Not Determined  68B − Not Determined  69 − Not Determined 70 + −  72 + −  73 ++ ++  74 + −  75 + −  92 ++ + 113 + − 117 ++ ++ 118++ + 119 − Not Determined 120 − Not Determined 121 − Not Determined 123++ + 124 + − 125 ++ + 126 + − 127 ++ + 128 ++ − 129 ++ + 130 + + 131 + +132 ++ + 133 ++ + 134 ++ + 135 ++ ++ 136 + − 137 ++ − 138 + + 139 + −140 + + 141 + − 142 ++ + 143 − Not Determined 144 + + 145 ++ + 146 ++ ++147 + − 148 + + 149 + − 150 ++ + 151 ++ + 152 ++ + 153 ++ + 154 + −155 + − 156 + Not Determined

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound, or a pharmaceutically acceptablesalt, hydrate or solvate thereof, of Formula (I):

wherein: R₁ is selected from —CO₂R₅, —C₁-C₅alkyl-CO₂R₅,—C₃-C₆-cycloalkyl-CO₂R₅, —NHCO₂R₅, —N(C₁-C₅ alkyl)-CO₂R₅, —O—CO₂R₅, or—C₁-C₅alkyl-O—CO₂R₅; R₂ is selected from H, —C₁-C₄alkyl,—C₃-C₆cycloalkyl, or —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl orcycloalkyl groups are optionally substituted with one or more groupsselected from halogen, —OH, or —O—C₁-C₅alkyl; n is 0, 1 or 2; Ring A issubstituted at one or more carbons with one, two, or three R₃substituents wherein each R₃ group is independently selected from H,halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl whereineach alkyl or cycloalkyl group is optionally substituted with one ormore groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or—O—C₁-C₅alkyl; Two R₃ groups on the same or different carbon atoms ofthe ring A may be optionally joined to form a spirocyclic or bicyclicring system with ring A; R₄ is selected from —C(O)—R₆, —CH₂R₆,—C(O)—CH═CH₂, —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃, —C(O)—CH═CHCH₂NR₇R₈,—C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl, wherein the alkyl orcycloalkyl groups may be optionally substituted with one or more groupsselected from —OH, halogen, alkyne, or —CN; R₅ is selected from—C₁-C₅alkyl, or —C₃-C₆cycloalkyl wherein the alkyl or cycloalkyl groupsmay be optionally substituted by one or more groups selected fromhalogen, —OH, or —O—C₁-C₅alkyl; R₆ is selected from —C₁-C₅alkyl,—C₃-C₆cycloalkyl, —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇R₈, —O-aryl,—O-heteroaryl, or heteroaryl wherein the alkyl, cycloalkyl, orheteroaryl groups can be optionally substituted by one or more groupsselected from halogen, —CN, alkyne, —OH, trifluoromethyl, —O—C₁-C₅alkyl,or —O—C₃-C₆cycloalkyl; R₇ and R₈ are independently selected from H,—C₁-C₅ alkyl, —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkylgroups may be optionally substituted by one or more groups selected fromhalogen, —OH, or —CN; and R₇ and R₈ may be optionally joined to form aring to form a heterocycle or with another heteroatom to form a ring. 2.The compound of claim 1, or a pharmaceutically acceptable salt, hydrateor solvate thereof, wherein: R₁ is —CO₂R₅.
 3. The compound of claim 1,or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: R₁ is —C₁-C₅-alkyl-CO₂R₅.
 4. The compound of claim 1, or apharmaceutically acceptable salt, hydrate or solvate thereof, wherein:R₁ is —C₃-C₆-cycloalkyl-CO₂R₅.
 5. The compound of claim 1, or apharmaceutically acceptable salt, hydrate or solvate thereof, wherein:R₁ is —NHCO₂R₅.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, wherein: R₁ is —N(C₁-C₅alkyl)-CO₂R₅.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, wherein: R₁ is —O—CO₂R₅. 8.The compound of claim 1, or a pharmaceutically acceptable salt, hydrateor solvate thereof, wherein: R₁ is —C₁-C₅alkyl-O—CO₂R₅.
 9. A compound,or a pharmaceutically acceptable salt, hydrate or solvate thereof, ofFormula (III):

wherein: R₁₀₀₀ is selected from —CO₂R₅₀₀₀, —C₁-C₅alkyl-CO₂R₅₀₀₀,—C₃-C₆-cycloalkyl-CO₂R₅₀₀₀, —NHCO₂R₅₀₀₀, —N(C₁-C₅ alkyl)-CO₂R₅₀₀₀,—O—CO₂R₅₀₀₀, or —C₁-C₅alkyl-O—CO₂R₅₀₀₀; R₂₀₀₀ is selected from H,—C₁-C₄alkyl, —C₃-C₆cycloalkyl, or —C₁-C₂alkyl-C₃-C₆cycloalkyl, whereinthe alkyl or cycloalkyl groups are optionally substituted with one ormore groups selected from halogen, —OH, or —O—C₁-C₅alkyl; n is 0, 1 or2; Ring Q is substituted at one or more carbons with one, two, or threeR₃₀₀₀ substituents wherein each R₃₀₀₀ group is independently selectedfrom H, halogen, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkylwherein each alkyl or cycloalkyl group is optionally substituted withone or more groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or—O—C₁-C₅alkyl; Two R₃₀₀₀ groups on the same or different carbon atoms ofthe ring Q may be optionally joined to form a spirocyclic or bicyclicring system with ring Q; R₄₀₀₀ is selected from —C(O)—R₆₀₀₀, —CH₂R₆₀₀₀,—C(O)—CH═CH₂, —C(O)—C(CH₂OCH₃)═CH₂, —C(O)—CH═CHCH₃,—C(O)—CH═CHCH₂NR₇₀₀₀R₈₀₀₀, —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl,wherein the alkyl or cycloalkyl groups may be optionally substitutedwith one or more groups selected from —OH, halogen, alkyne, or —CN;R₅₀₀₀ is selected from H, —C₁-C₅alkyl, and —C₃-C₆cycloalkyl wherein thealkyl or cycloalkyl groups may be optionally substituted by one or moregroups selected from halogen, —OH, —C₃-C₅ cycloalkyl, or —O—C₁-C₅alkyl;R₆₀₀₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,—C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₀₀₀R₈₀₀₀, —O-aryl, —O-heteroaryl, orheteroaryl wherein the alkyl, cycloalkyl, or heteroaryl groups can beoptionally substituted by one or more groups selected from halogen, —CN,alkyne, —OH, trifluoromethyl, —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;R₇₀₀₀ and R₈₀₀₀ are independently selected from H, —C₁-C₅ alkyl, —C₁-C₅alkoxy, or —C₃-C₅ cycloalkyl where the alkyl groups may be optionallysubstituted by one or more groups selected from halogen, —OH, —CN, or—C₃-C₅ cycloalkyl; R₇₀₀₀ and R₈₀₀₀ may be optionally joined to form aring to form a heterocycle or with another heteroatom to form a ring.10. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


11. The compound of claim 9, wherein the compound is selected from thegroup consisting of:


12. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, a pharmaceutically acceptable saltthereof, a derivative thereof, or a combination thereof; and apharmaceutically acceptable carrier.
 13. A method of treating a JAK1-and/or JAK3-mediated disease in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound of claim 1, a derivative thereof, or a combination thereof. 14.The method of claim 13, further comprising administering anothertherapeutic agent.
 15. The method of claim 13, wherein said JAK1- and/orJAK3-mediated disease is selected from the group consisting of anautoimmune disorder, broad activation of the immune responses, bacterialinfection, viral infection, inflammation, a chronic inflammatorydisorder, an acute inflammatory disorder or condition, anauto-inflammatory disorder, a fibrotic disorders, a metabolic disorders,a neoplasm, a cardiovascular disorders, a cerebrovascular disorders, askin disorder, pruritus, a hair loss disorder, a cancer, autoimmuneconnective tissue disease, an autoimmune condition, Still's disease,adult-onset Still's disease, Th17-associated inflammation,polychondritis, relapsing polychondritis, myositis, polymyositis,autoimmune myositis, dermatomyositis, juvenile dermatomyositis,myasthenia gravis, Arthritis, rheumatoid arthritis, juvenile rheumatoidarthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis,infectious arthritis, inflammatory arthritis, inflammatory boweldisease-associated arthritis, idiopathic arthritis, juvenile idiopathicarthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis,spondylitis/spondyloarthritis/spondyloarthropathy, ankylosingspondylitis, gout, scleroderma, systemic scleroderma, juvenilescleroderma, Reiter's syndrome/reactive arthritis, lyme disease,lupus/systemic lupus erythematosus (SLE), lupus erythematosus, pediatricsystemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus,chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus,polymyalgia rheumatica, enthesitis, mixed connective tissue disease,enthesopathy, carditis, myocarditis, angiogenesis disorders,myelodysplastic syndrome, atherosclerosis, restenosis, restenosis of anatherosclerotic coronary artery, acute coronary syndrome, myocardialinfarction, cardiac-allograft vasculopathy, transplant arteriopathy,vasculitis, large vessel vasculitis, small vessel vasculitis, giant-cellarteritis, polyarteritis nodosa, vasculitis syndromes, Takayasu'sarteritis, Wegener's granulomatosis, Behcet's Disease, stimulator ofinterferon genes (STING) associated vasculopathy with onset in infancy(SAVI), a gastrointestinal disorder, enterocolitis, colitis,inflammatory bowel disease, ulcerative colitis, Crohn's disease,irritable bowel syndrome, enteritis syndrome/spastic colon, celiacdisease, acute and chronic pancreatitis, primary biliary cirrhosis,primary sclerosing cholangitis, jaundice, cirrhosis, primary biliarycirrhosis, cirrhosis due to fatty liver disease, alcoholic andnonalcoholic steatosis, esophagitis, gastritis, gastric and duodenalulcers, peritonitis, Nephropathy, immunologically mediatedglomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy,a chronic progressive nephropathy, diabetic kidney disease/diabeticnephropathy, renal fibrosis, renal ischemic/reperfusion injury, HIVassociated nephropathy, ureteral obstructive nephropathy,glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidneydisease, autosomal dominant polycystic kidney disease,glomerulonephritis, chronic kidney disease, diabetic nephropathy,hypertension induced nephropathy, diabetic kidney disease, lupusnephritis, interstitial cystitis periodontitis, gingivitis pulmonaryinflammation, sinusitis, pneumonia, bronchitis, asthma, bronchialasthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans,chronic obstructive pulmonary disease (COPD), interstitial lung disease,pulmonary fibrosis, idiopathic pulmonary fibrosis, acute lung injury,cystic fibrosis, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, Meniere's disease, an ocular disorder, ocular inflammation,uveitis, dry eye/keratoconjunctivitis sicca, scleritis, episcleritis,keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis,retinopathy, diabetic retinopathy, immune mediated retinopathy, maculardegeneration, wet macular degeneration, age related maculardegeneration, Mastocytosis, iron deficiency anemia, uremia,hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD),myelodysplastic syndrome, idiopathic thrombocytic pupura, boneresorption diseases, a Neurodegenerative disorder, aneurological/neuromuscular disorders, multiple sclerosis, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis (ALS),familial ALS, sporadic ALS, Alzheimer's disease, myasthenia gravis,Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barret syndrome,meningitis, encephalitis, traumatic brain injury, nervous system damage,delusional parasitosis, dysregulation of neuronal processes and sensoryperception, stroke/neuronal ischemia, spinal cord injury, peripheralneuropathy, tactile hallucinations, spinal cord injury, psychiatricdisease, pain, acute pain, chronic pain, neuropathic pain, fibromyalgia,paresthetica, nerve irritation, peripheral neuropathy, pruritus/itchatopic pruritus, xerotic pruritus, pruritus associated withpsoriasis/psoriatic itch/psoriasis-associated itch, acute pruritus,chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliaryitch, hepatobiliary-associated itch, renal associated itch/renal itch,uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichensimplex chronicus associated pruritus, lymphoma-associated itch,leukemia-associated itch, prurigo nodularis, atopicdermatitis-associated itch, atopic itch/atopic puritis, bullous itch,brachioradial pruritus, neurogenic itch, neuropathic itch, notalgiaparesthetica, pruritic popular eruption of HIV, psychogenic itch,swimmer's itch, pruritus or uremic itch, urticarial itch, a dermatologicdisorders, dermatologic drug reactions/drug eruptions, xerosis/dry skin,skin rash, skin sensitization, skin irritation, sunburn, shaving, bodylouse, head lice/pediculosis, pubic lice, cutaneous larva migrans,scabies, parasitic infection, insect infestation, urticarial/hives,popular uritcaria, insect bites, insect stings, dandruff, fungalinfection, herpes, varicella/chicken pox, eosinophilic folliculitis,dermatosis of pregnancy/pruritic urticarial papules and plaques ofpregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses,histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis,psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne,acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne,scarring acne, acne keloidalis nuchae, atopies, allergic contactsensitization, allergic dermatitis, dermatitis, atopicdermatitis/eczema, contact dermatitis, photodermatitis, seborrheicdermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis(Sweet's syndrome), chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperature syndrome (CANDLE Syndrome),hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia, eyebrowalopecia, intranasal hair alopecia, scarring alopecia, centralcentrifugal cicatricial alopecia, nonscarring alopecia, alopecia areata(AA), patchy AA, alopecia totalis (AT), alopecia universalis (AU),ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata,androgenetic/androgenic alopecia (AGA)/male and female pattern AGA,telogen effluvium, tinea capitis, hypotrichosis, hereditaryhypotrichosis simplex, lichen planopilaris, frontal fibrosing alopecia,punctate palmoplantar keratoderma, erythema elevatinum diutinum (EED),neutrophilic eccrine hidradenitis, palisading neutrophilic granulomatousdermatitis, neutrophilic urticarial dermatosis, vitiligo, segmentalvitiligo, unisegmental vitiligo, bisegmental vitiligo, multisegmentalvitiligo, non-segmental vitiligo, acral, facial, acrofacial vitiligo,centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichromevitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, bluevitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo,universal vitiligo, mixed vitiligo/nonsegmental associated withsegmental vitiligo, focal vitiligo, solitary mucosal vitiligo, vitiligowith or without leukotricia, bullous diseases, immunobullous diseases,bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linearIgA disease, gestational pemphigoid, xeroderma pigmentosum, disorders offibrosis and scarring, fibroids, hepatic fibrosis, low grade scarring,scleroderma, increased fibrosis, keloids, post-surgical scars, woundhealing, surgical scarring, radiation induced fibrosis, CNS scarring,alimentary track or gastrointestinal fibrosis, renal fibrosis, hepaticor biliary fibrosis, liver fibrosis, cardiac fibrosis, ophthalmicscarring, fibrosclerosis, scar growth, wound or scab healing, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis/Ormond'sdisease, progressive massive fibrosis, nephrogenic systemic fibrosis,Sjorgren's syndrome, sarcoidosis, familial Mediterranean fever,Cryopyrin associated periodic syndrome, Muckle-Wells syndrome, familialcold auto-inflammatory syndrome/familial cold uticaria/TNF receptorassociated periodic syndrome, neonatal-onset multisystem inflammatorydisease, hyperoxia induced inflammation, reperfusion injury,post-surgical trauma, tissue injury, elevated temperature syndrome,diabetes, Type I diabetes, Type II diabetes, diabetes mellitus,Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman'sdisease, hyperparathyroidism, menopause, obesity, steroid-resistance,glucose intolerance, metabolic syndrome, thyroid illness, hypophysitis,systemic immune senescence, autoimmune atrophic gastritis, autoimmuneatrophic gastritis of pernicious anemia, autoimmune encephalomyelitis,autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome,autoimmune thrombocytopenia, sympathetic ophthalmia, secondaryhematologic manifestations of autoimmune diseases, autoimmune hemolyticsyndromes, autoimmune hemolytic anemia, autoimmune and inflammatoryhepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia,silicone implant associated autoimmune disease, drug-inducedautoimmunity, HIV-related autoimmune syndrome, metal-inducedautoimmunity, autoimmune deafness, autoimmune thyroid disorders, allergyand allergic reactions, a Type I hypersensitivity reactions, a Type IIhypersensitivity reactions, a Type III hypersensitivity reactiondiseases, a Type IV hypersensitivity reaction, acute and chronicinfection, sepsis syndrome, sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome, graft vs. hostreaction/graft vs. host disease, allograft rejection, earlytransplantation rejection, lymphoma, leukemia, multiple myeloma, a solidtumor, teratoma, metastatic cancer, a bone disorders, internal cancer,bone cancer, mouth/pharynx cancer, esophagus cancer, larynx cancer,stomach cancer, intestinal cancer, colon cancer, rectum cancer, lungcancer, liver cancer, pancreas cancer, nerve cancer, brain cancer, headand neck cancer, throat cancer, ovary cancer, uterus cancer, prostatecancer, testis cancer, bladder cancer, kidney cancer, breast cancer,gall bladder cancer, cervix cancer, thyroid cancer, prostate cancer, eyecancer, skin cancer, a fibrotic cancer, fibroma, fibroadenomas,fibrosarcoma, a myeloproliferative disorder, neoplasm, hematopoieticneoplasm, a myeloid neoplasm, a lymphoid neoplasm, myelofibrosis,primary myelofibrosis, polycythemia vera, essential thrombocythemia,acute lymphocytic leukemia, acute and chronic myelogenous leukemia,chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronicmyelomonocytic leukemia (CMML), or promyelocytic leukemia, multiplemyeloma, a myeloid malignancy myeloid metaplasia with myelofibrosis(MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF),Hodgkin's disease, cutaneous lymphoma, cutaneous T-cell lymphoma,mycosis fungoides, B-cell lymphoma, T-cell lymphoma, mantle celllymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors,Hodgkin's disease, non-Hodgkin's disease, Kaposi's sarcoma,rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroidfollicular cancer, increased accumulation of exogenous opioids orsynthetic opioids, notalgia paraesthetica, obsessive-compulsivedisorders, nostalgia associated with obsessive-compulsive disorders, anda combination thereof.
 16. The method of claim 14, wherein the othertherapeutic agent is selected from a chemotherapeutic agent, ananti-proliferative agent, an anti-inflammatory agent, animmunomodulatory agent, immunosuppressive agent, a neurotrophic factor,an agent for treating cardiovascular disease, an agent for treatingdiabetes, an agent for treating immunodeficiency disorders, and acombination thereof.
 17. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 9, apharmaceutically acceptable salt thereof, a derivative thereof, or acombination thereof and a pharmaceutically acceptable carrier.
 18. Amethod of treating a JAK1- and/or JAK3-mediated disease in a subject inneed thereof comprising administering to the subject a therapeuticallyeffective amount of a compound of claim 9, a derivative thereof, or acombination thereof.
 19. The method of claim 18, further comprisingadministering another therapeutic agent.
 20. The method of claim 18,wherein said JAK1- and/or JAK3-mediated disease is selected from thegroup consisting of an autoimmune disorder, broad activation of theimmune responses, bacterial infection, viral infection, inflammation, achronic inflammatory disorder, an acute inflammatory disorder orcondition, an auto-inflammatory disorder, a fibrotic disorder, ametabolic disorder, a neoplasm, a cardiovascular disorder, acerebrovascular disorder, a skin disorder, pruritus, a hair lossdisorder, a cancer, autoimmune connective tissue disease, an autoimmunecondition, Still's disease, adult-onset Still's disease, Th17-associatedinflammation, polychondritis, relapsing polychondritis, myositis,polymyositis, autoimmune myositis, dermatomyositis, juveniledermatomyositis, myasthenia gravis, Arthritis, rheumatoid arthritis,juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoidarthritis, osteoarthritis, infectious arthritis, inflammatory arthritis,inflammatory bowel disease-associated arthritis, idiopathic arthritis,juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis,psoriatic arthritis, spondylitis/spondyloarthritis/spondyloarthropathy,ankylosing spondylitis, gout, scleroderma, systemic scleroderma,juvenile scleroderma, Reiter's syndrome/reactive arthritis, lymedisease, lupus/systemic lupus erythematosus (SLE), lupus erythematosus,pediatric systemic lupus erythematosus, cutaneous lupus, subacutecutaneous lupus, chronic cutaneous lupus/discoid lupus, chilblain lupuserythematosus, polymyalgia rheumatica, enthesitis, mixed connectivetissue disease, enthesopathy, carditis, myocarditis, angiogenesisdisorders, myelodysplastic syndrome, atherosclerosis, restenosis,restenosis of an atherosclerotic coronary artery, acute coronarysyndrome, myocardial infarction, cardiac-allograft vasculopathy,transplant arteriopathy, vasculitis, large vessel vasculitis, smallvessel vasculitis, giant-cell arteritis, polyarteritis nodosa,vasculitis syndromes, Takayasu's arteritis, Wegener's granulomatosis,Behcet's Disease, stimulator of interferon genes (STING) associatedvasculopathy with onset in infancy (SAVI), a gastrointestinal disorder,enterocolitis, colitis, inflammatory bowel disease, ulcerative colitis,Crohn's disease, irritable bowel syndrome, enteritis syndrome/spasticcolon, celiac disease, acute and chronic pancreatitis, primary biliarycirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis, primarybiliary cirrhosis, cirrhosis due to fatty liver disease, alcoholic andnonalcoholic steatosis, esophagitis, gastritis, gastric and duodenalulcers, peritonitis, Nephropathy, immunologically mediatedglomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy,a chronic progressive nephropathy, diabetic kidney disease/diabeticnephropathy, renal fibrosis, renal ischemic/reperfusion injury, HIVassociated nephropathy, ureteral obstructive nephropathy,glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidneydisease, autosomal dominant polycystic kidney disease,glomerulonephritis, chronic kidney disease, diabetic nephropathy,hypertension induced nephropathy, diabetic kidney disease, lupusnephritis, interstitial cystitis, periodontitis, gingivitis, pulmonaryinflammation, sinusitis, pneumonia, bronchitis, asthma, bronchialasthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans,chronic obstructive pulmonary disease (COPD), interstitial lung disease,pulmonary fibrosis, idiopathic pulmonary fibrosis, acute lung injury,cystic fibrosis, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, Meniere's disease, an ocular disorder, ocular inflammation,uveitis, dry eye/keratoconjunctivitis sicca, scleritis, episcleritis,keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis,retinopathy, diabetic retinopathy, immune mediated retinopathy, maculardegeneration, wet macular degeneration, dry age related maculardegeneration, Mastocytosis, iron deficiency anemia, uremia,hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD),myelodysplastic syndrome, idiopathic thrombocytic pupura, boneresorption diseases, a Neurodegenerative disorder, aneurological/neuromuscular disorder, multiple sclerosis, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis (ALS),familial ALS, sporadic ALS, Alzheimer's disease, myasthenia gravis,Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barret syndrome,meningitis, encephalitis, traumatic brain injury, nervous system damage,delusional parasitosis, dysregulation of neuronal processes and sensoryperception, stroke/neuronal ischemia, spinal cord injury, peripheralneuropathy, tactile hallucinations, spinal cord injury, psychiatricdisease, pain, acute pain, chronic pain, neuropathic pain, fibromyalgia,paresthetica, nerve irritation, peripheral neuropathy, pruritus/itchatopic pruritus, xerotic pruritus, pruritus associated withpsoriasis/psoriatic itch/psoriasis-associated itch, acute pruritus,chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliaryitch, hepatobiliary-associated itch, renal associated itch/renal itch,uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichensimplex chronicus associated pruritus, lymphoma-associated itch,leukemia-associated itch, prurigo nodularis, atopicdermatitis-associated itch, atopic itch/atopic puritis, bullous itch,brachioradial pruritus, neurogenic itch, neuropathic itch, notalgiaparesthetica, pruritic popular eruption of HIV, psychogenic itch,swimmer's itch, pruritus or uremic itch, urticarial itch, a dermatologicdisorder, dermatologic drug reactions/drug eruptions, xerosis/dry skin,skin rash, skin sensitization, skin irritation, sunburn, shaving, bodylouse, head lice/pediculosis, pubic lice, cutaneous larva migrans,scabies, parasitic infection, insect infestation, urticarial/hives,popular uritcaria, insect bites, insect stings, dandruff, fungalinfection, herpes, varicella/chicken pox, eosinophilic folliculitis,dermatosis of pregnancy/pruritic urticarial papules and plaques ofpregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses,histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis,psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne,acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne,scarring acne, acne keloidalis nuchae, atopies, allergic contactsensitization, allergic dermatitis, dermatitis, atopicdermatitis/eczema, contact dermatitis, photodermatitis, seborrheicdermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis(Sweet's syndrome), chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperature syndrome (CANDLE Syndrome),hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia, eyebrowalopecia, intranasal hair alopecia, scarring alopecia, centralcentrifugal cicatricial alopecia, nonscarring alopecia, alopecia areata(AA), patchy AA, alopecia totalis (AT), alopecia universalis (AU),ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata,androgenetic/androgenic alopecia (AGA)/male and female pattern AGA,telogen effluvium, tinea capitis, hypotrichosis, hereditaryhypotrichosis simplex, lichen planopilaris, frontal fibrosing alopecia,punctate palmoplantar keratoderma, erythema elevatinum diutinum (EED),neutrophilic eccrine hidradenitis, palisading neutrophilic granulomatousdermatitis, neutrophilic urticarial dermatosis, vitiligo, segmentalvitiligo, unisegmental vitiligo, bisegmental vitiligo, multisegmentalvitiligo, non-segmental vitiligo, acral, facial, acrofacial vitiligo,centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichromevitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, bluevitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo,universal vitiligo, mixed vitiligo/nonsegmental associated withsegmental vitiligo, focal vitiligo, solitary mucosal vitiligo, vitiligowith or without leukotricia, bullous diseases, immunobullous diseases,bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linearIgA disease, gestational pemphigoid, xeroderma pigmentosum, disorders offibrosis and scarring, fibroids, hepatic fibrosis, low grade scarring,scleroderma, increased fibrosis, keloids, post-surgical scars, woundhealing, surgical scarring, radiation induced fibrosis, CNS scarring,alimentary track or gastrointestinal fibrosis, renal fibrosis, hepaticor biliary fibrosis, liver fibrosis, cardiac fibrosis, ophthalmicscarring, fibrosclerosis, scar growth, wound or scab healing, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis/Ormond'sdisease, progressive massive fibrosis, nephrogenic systemic fibrosis,Sjorgren's syndrome, sarcoidosis, familial Mediterranean fever,Cryopyrin associated periodic syndrome, Muckle-Wells syndrome, familialcold auto-inflammatory syndrome/familial cold uticaria/TNF receptorassociated periodic syndrome, neonatal-onset multisystem inflammatorydisease, hyperoxia induced inflammation, reperfusion injury,post-surgical trauma, tissue injury, elevated temperature syndrome,diabetes, Type I diabetes, Type II diabetes, diabetes mellitus,Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman'sdisease, hyperparathyroidism, menopause, obesity, steroid-resistance,glucose intolerance, metabolic syndrome, thyroid illness, hypophysitis,systemic immune senescence, autoimmune atrophic gastritis, autoimmuneatrophic gastritis of pernicious anemia, autoimmune encephalomyelitis,autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome,autoimmune thrombocytopenia, sympathetic ophthalmia, secondaryhematologic manifestations of autoimmune diseases, autoimmune hemolyticsyndromes, autoimmune hemolytic anemia, autoimmune and inflammatoryhepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia,silicone implant associated autoimmune disease, drug-inducedautoimmunity, HIV-related autoimmune syndromes, metal-inducedautoimmunity, autoimmune deafness, autoimmune thyroid disorders, allergyand allergic reactions, a Type I hypersensitivity reactions, a Type IIhypersensitivity reactions, a Type III hypersensitivity reactiondisease, and a Type IV hypersensitivity reaction, acute and chronicinfection, sepsis syndrome, sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome, graft vs. hostreaction/graft vs. host disease, allograft rejection, earlytransplantation rejection, lymphoma, leukemia, multiple myeloma, a solidtumor, teratoma, metastatic cancer, a bone disorders, internal cancer,bone cancer, mouth/pharynx cancer, esophagus cancer, larynx cancer,stomach cancer, intestinal cancer, colon cancer, rectum cancer, lungcancer, liver cancer, pancreas cancer, nerve cancer, brain cancer, headand neck cancer, throat cancer, ovary cancer, uterus cancer, prostatecancer, testis cancer, bladder cancer, kidney cancer, breast cancer,gall bladder cancer, cervix cancer, thyroid cancer, prostate cancer, eyecancer, skin cancer, a fibrotic cancer, fibroma, fibroadenomas,fibrosarcoma, a myeloproliferative disorder, neoplasm, hematopoieticneoplasm, a myeloid neoplasm, a lymphoid neoplasm, myelofibrosis,primary myelofibrosis, polycythemia vera, essential thrombocythemia,acute lymphocytic leukemia, acute and chronic myelogenous leukemia,chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronicmyelomonocytic leukemia (CMML), or promyelocytic leukemia, multiplemyeloma, a myeloid malignancy myeloid metaplasia with myelofibrosis(MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF),Hodgkin's disease, cutaneous lymphoma, cutaneous T-cell lymphoma,mycosis fungoides, B-cell lymphoma, T-cell lymphoma, mantle celllymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors,Hodgkin's disease, non-Hodgkin's disease, Kaposi's sarcoma,rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroidfollicular cancer, increased accumulation of exogenous opioids orsynthetic opioids, notalgia paraesthetica, obsessive-compulsivedisorders, nostalgia associated with obsessive-compulsive disorders, anda combination thereof.
 21. The method of claim 19, wherein the othertherapeutic agent is selected from a chemotherapeutic agent, ananti-proliferative agent, an anti-inflammatory agent, animmunomodulatory agent, immunosuppressive agent, a neurotrophic factor,an agent for treating cardiovascular disease, an agent for treatingdiabetes, an agent for treating immunodeficiency disorders, and acombination thereof.